载脂蛋白A5调节甘油三酯代谢机制及其临床意义
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摘要
背景:
血浆甘油三酯(TG)升高是冠心病的独立危险因素,引起高甘油三酯血症(HTG)常见原因包括高果糖饮食、急性期反应(APR)、代谢综合征(MS)等。降低TG可有效防止冠心病,目前可降低TG的降脂药物主要有:他汀类、贝特类和血脂康等。
载脂蛋白A5(ApoA5)是新发现的载脂蛋白超家族成员,大量研究均证实,ApoA5可显著降低血浆TG。过氧化物酶体增殖物激活受体-α(PPARα)和肝X受体-α(LXRα)是调节ApoA5表达的两个关键核受体,其中,前者上调ApoA5表达,而后者下调ApoA5表达。
然而,目前尚不清楚高果糖饮食、急性期反应以及代谢综合征诱导的HTG是否与ApoA5有关;也不知他汀类、贝特类或血脂康降低TG是否通过ApoA5而起作用。
目的:
明确高果糖饮食、急性期反应以及代谢综合征诱导的HTG是否与ApoA5有关,明确非诺贝特、阿托伐他汀和血脂康降TG作用是否与调节ApoA5有关,并探讨核受体PPARα和LXRα对ApoA5表达的调节作用。
方法:
一.果糖诱导性高甘油三血症的动物和体外实验
40只健康雄性Sprague-Dawley大鼠,随机分为五组(n=8/组):(1)对照组:正常普通饮食喂养;(2)HTG组:10%果糖水喂养2周建立高HTG大鼠模型,并继续喂养4周;(3)贝特组:HTG大鼠建模后,加予非诺贝特(100 mg/kg/天)干预4周;(4)他汀组:HTG大鼠建模后,加予阿托伐他汀(10 mg/kg/天)干预4周;(5)联合组:HTG大鼠建模后,加予非诺贝特(100 mg/kg/天)和阿托伐他汀(10mg/kg/天)干预4周。分别在0周、2周及6周测定体重和空腹血脂。6周后取动物肝脏组织标本,采用免疫组化、逆转录多聚酶链式反应(RT-PCR)及免疫印迹(WB)测定肝脏ApoA5的基因和蛋白表达,同时采用RT-PCR和WB测定肝脏PPARα和LXRα的基因和蛋白表达。
以HepG2细胞为模型,观察果糖、非诺贝特和阿托伐他汀干预后,细胞TG浓度变化,ApoA5、PPARα和LXRα表达的改变,并通过PPARα或LXRα的激动剂或抑制剂干预,揭示三者调控ApoA5表达的机制。
二.急性期反应性高甘油三酯血症的临床、动物及体外实验
(一)ACS临床试验
入选228例ACS患者和232名健康者作为研究对象,抽血分离血浆,采用酶联免疫吸附检测(ELISA)测定ApoA5血浆浓度,同时测定血浆C-反应蛋白和血脂水平。
(二)急性炎症动物和体外实验
32只6周龄健康雌性C57BL/6鼠,随机分为4组(n=8/组):(1)对照组,普通饮食喂养;(2)炎症组,普通饮食喂养4周后,腹腔注射100μg脂多糖(LPS)以建立急性炎症模型;(3)他汀组:阿托伐他汀(10 mg/kg/天)干预4周后,腹腔注射LPS;(4)贝特组,非诺贝特(100 mg/kg/天)干预4周后,腹腔注射LPS。分别在实验第0周、第4周注射LPS前、以及注射LPS后测定空腹血脂和肿瘤坏死因子-α(TNFα)血浆水平。注射LPS后取动物肝脏组织标本,采用RT-PCR和WB测定肝脏ApoA5和PPARα的基因和蛋白表达。
体外观察人重组TNFα对HepG2细胞TG及ApoA5和PPARα表达的影响,同时观察阿托伐他汀和非诺贝特对TNFα刺激下肝细胞ApoA5表达的影响及其机制。
三.血脂康降低冠心病患者甘油三酯的机制研究
(一)血脂康降脂临床试验
入选60例稳定性冠心病患者,随机分为两组,即血脂康组和对照组,分别接受血脂康(600 mg/次,一天两次)和安慰剂治疗,疗程共6周。实验前和实验第6周,采用ELISA测定血浆ApoA5浓度,同时测定空腹血脂水平。
(二)动物和细胞实验
32只健康雄性Sprague-Dawley大鼠,随机分为四组(n=8/组):(1)对照组:正常普通饮食喂养;(2)高甘油三酯血脂(HTG)组:10%果糖水喂养2周建立HTG大鼠模型,并继续喂养4周;(3)血脂康低剂量(L-XZK)组,10%果糖水喂养2周建立HTG大鼠模型后,加予血脂康20 mg/kg/天进行药物干预,干预4周;(4)血脂康高剂量(H-XZK)组,建立HTG大鼠模型后,加予血脂康40 mg/kg/天进行药物干预,干预4周。分别在实验前(0周)、实验后2周及6周测定空腹血脂水平。分别采用RT-PCR和WB测定肝脏ApoA5、PPARα和LXRα的基因和蛋白表达。
体外观察血脂康干预对HepG2细胞TG、以及ApoA5、PPARα和LXRα表达的影响及其机制。
四.代谢综合征临床、动物及体外实验
(一)代谢综合征临床试验
入选340例代谢综合征(MS)患者和342名健康者作为研究对象,采用ELISA测定ApoA5血浆浓度,同时测定空腹血脂、血糖和胰岛素,计算胰岛素抵抗指数(HOMA-IR)。
(二)动物和细胞实验
24只8周龄的健康雄性Sprague-Dawley大鼠,随机分为3组(n=8/组):(1)对照组:普通饮食;(2)MS组:高果糖饮食(含60%果糖),喂养7周;(3)贝特组:高果糖饮食加予非诺贝特100mg/kg/天,干预7周。分别在实验第0周和第7周测定空腹血脂和尾动脉血压,并通过高胰岛素正常血糖钳夹技术测定胰岛素敏感性。实验结束时,取动物肝脏组织标本,采用RT-PCR和WB测定肝脏ApoA5的基因和蛋白表达。
通过高浓度胰岛素诱导HepG2细胞,构建胰岛素抵抗(IR)肝细胞模型,体外观察胰岛素抵抗状况下肝细胞的ApoA5表达和TG变化,探讨非诺贝特对IR状况下肝细胞ApoA5表达的影响及其机制。
结果:
一.果糖诱导性高甘油三酯血症动物和体外实验结果
1.6周后,HTG组大鼠血浆TG显著升高,而药物治疗组TG均显著降低,降低程度依次为:他汀组＜贝特组＜联合组(P＜0.05);相反,HTG组大鼠ApoA5基因和蛋白表达显著降低,而药物治疗组ApoA5表达均显著升高,升高程度依次为:他汀组＜贝特组＜联合组(P＜0.05);与动物实验一致,果糖显著抑制HepG2细胞的ApoA5基因和蛋白表达、升高细胞TG,而药物干预可上调ApoA5表达,降低TG,且疗效显著程度依次为:他汀组＜贝特组＜联合组(P＜0.05)。
2.HTG组大鼠肝脏PPARα基因表达显著下调,而药物治疗组PPARα基因表达显著升高,升高程度依次为:他汀组＜贝特组＜联合组(P＜0.05),但各组大鼠PPARα蛋白表达无显著差异;果糖显著抑制细胞PPARα基因和蛋白表达,而药物干预可上调PPARα基因和蛋白表达,且疗效显著程度依次为:他汀组＜贝特组＜联合组(P＜0.05)。
3.HTG组和贝特组大鼠肝脏LXRα基因表达显著升高,而他汀组LXRα基因表达显著降低(P＜0.01),联合组LXRα基因表达与对照组无显著差异,但各组LXRα蛋白表达无显著差异;果糖和贝特均可上调LXRα基因和蛋白表达,而他汀抑制LXRα表达,联合组LXRα表达与对照组无显著差异。
二.急性期反应性高甘油三血症临床、动物及体外实验结果
1.与对照组比较,ACS患者ApoA5、TG和CRP显著升高(P＜0.05)。
2.ACS患者血浆ApoA5与TG(r=0.642,P＜0.001)和CRP(r=0.594,p＜0.001)均呈显著正相关,且其TG与CRP(r=0.572,P＜0.01)显著正相关。
3.多元Logistic分析显示ApoA5血浆水平可能是ACS保护因素(OR=0.82,95%CI 0.70-0.95,P=0.02)。
4.注射LPS后,炎症组小鼠TG显著升高,而TC、HDL-C和LDL-C显著降低(P＜0.001);而他汀和贝特减轻了炎症引起的上述血脂变化幅度(P＜0.05)。
5.注射LPS后,炎症组小鼠肝脏ApoA5基因和蛋白表达显著升高,而PPARα基因和蛋白表达显著下降(P＜0.01);同样,他汀和贝特减轻了炎症引起的ApoA5和PPARα表达变化幅度(P＜0.05)。
6.TNFα刺激后,HepG2细胞TG显著升高(P＜0.001),而他汀和贝特可以改善TNFα引起的细胞TG升高(P＜0.05)。
7.TNFα刺激可上调HepG2细胞ApoA5基因和蛋白表达,但却抑制PPARα基因和蛋白表达;相反,他汀和贝特一方面可减少TNFα引起的ApoA5表达上调,另一方面可逆转TNFα引起的PPARα表达下降P＜0.05)。
三.血脂康降低冠心病患者甘油三酯的机制研究结果
1.血脂康治疗后,冠心病患者血浆TG显著下降,而ApoA5显著升高;所有冠心病患者ApoA5和TG显著负相关(P＜0.001)。
2.血脂康剂量依赖性升高大鼠肝脏ApoA5基因和蛋白表达,降低血浆TG;血脂康剂量依赖性升高大鼠肝脏PPARα基因表达,抑制LXRα基因表达(P＜0.05)。
3.血脂康显著升高HepG2细胞的ApoA5基因和蛋白表达,降低细胞TG(P＜0.01);PPARα抑制剂或LXRα激动剂显著抑制血脂康上调ApoA5表达作用(P＜0.05)。
四.代谢综合征临床、动物及体外实验
1.与对照组比较,MS患者血浆ApoA5显著降低、TG显著升高,且二者显著负相关(P＜0.05);MS患者HOMA-IR显著升高,且与ApoA5显著负相关(P＜0.05)。
2.多元Logistic分析显示ApoA5血浆水平可能是MS保护因素(OR=0.77,95%CI 0.64-0.92,P=0.04)。
3.与对照组比较,MS大鼠胰岛素敏感性显著下降,而肝脏ApoA5基因和蛋白表达显著下降(P均＜0.05)。
4.非诺贝特干预后,MS大鼠胰岛素敏感性明显增加,TG显著下降,而肝脏ApoA5基因和蛋白表达显著升高(P均＜0.05)。
5.高浓度胰岛素诱导下,HepG2细胞ApoA5基因和蛋白表达显著下降,而TG显著升高;非诺贝特可有效逆转高浓度胰岛素所导致的细胞ApoA5表达下调,降低TG,但加入PPARα抑制剂后,非诺贝特的上述治疗作用丧失(P均＜0.05)。
结论:
1.果糖通过抑制PPARα并上调LXRα表达,抑制肝脏ApoA5表达,诱导HTG;非诺贝特和阿托伐他汀均通过上调ApoA5表达,治疗果糖诱导性HTG,且二者在ApoA5表达调控上存在机制互补性。
2.急性期反应可升高血浆TG,此时ApoA5也显著升高,但可能是机体的一种代偿,与此时PPARα表达下调关系不大;非诺贝特和阿托伐他汀均能降低急性炎症所致TG升高,但该作用不完全通过ApoA5途径,而与二者抗炎作用有关。
3.血脂康通过上调PPARα并抑制LXRα表达,升高ApoA5肝脏表达和血浆水平,降低TG。
4.MS时,ApoA5肝脏表达和血浆水平降低,导致TG升高,增加MS风险;非诺贝特通过升高ApoA5、改善IR,降低MS大鼠血浆TG。
Background:
Elevated plasma triglyceride(TG) is an independent risk factor of coronary heart disease.The common causes for hypertriglyceridemia (HTG) include high fructose diet,acute phase response(APR) and metabolic syndrome(MS).Plasma TG reduction will help to prevent coronary heart disease.
Therefore,it will help to reduce the morbidity and mortality of coronary heart disease by the treatment of high fructose diet-induced HTG.However,the underlying mechanism for high fructose diet-induced HTG remains to be clarified.Fibrate,statin and Xuezhikang are three clinically widely-used hypotriglyceridemic agents.
The recently identified apolipoprotein A5(apoA5) is implicated in TG-lowering by the considerable body of data.Peroxisome proliferator-activated receptor-α(PPARα) and liver X receptor-α(LXRα) are two key nuclear receptors in regulation of apoA5 expression.PPARαcan upregulate apoA5 expression but otherwise for LXRα.
However,it is unclear for the role of apoA5 in HTG induced by high fructose diet,APR and MS.Furthermore,it remains unknown the association of apoA5 with the hypotriglyceridemic effects of fibrate, statin and Xuezhikang.
Objective:
The aim of this study was to define the role of apoA5 in HTG induced by high fructose diet,APR and MS;to investigate the association of apoA5 with the hypotriglyceridemic effects of fibrate,statin and Xuezhikang;to determine the involvement of PPARαand LXRα.
Methods:
Ⅰ.Animal and cell experiments for fructose-induced HTG
Forty healthy male Sprague-Dawley rats were randomized into five groups(n=8 each group):(1) control group,with no special treatment;(2) fructose group,with 10%fructose water for two weeks to establish animal HTG model,and with 10%fructose water for next four weeks;(3) fibrate group,with 10%fructose water for two weeks and supplemented with fenofibrate 100 mg/kg/d for next four weeks;(4) statin group,with 10%fructose water for two weeks and supplemented with atorvastatin 10 mg/kg/d for next four weeks;and(5) combination group,with 10% fructose water for two weeks and supplemented with fenofibrate 100 mg/kg/d and atorvastatin 10 mg/kg/d for next four weeks.The measurements were performed at 0,2 and 6 week for weight and fasting plasma lipids,blood sugar and insulin in animals.Liver samples were obtained at 6 week.The expressions of hepatic apoA5 gene and protein were measured using immunohistochemistry,RT-PCR and Western Blot analysis respectively.Besides,hepatic expressions of PPARαand LXRα were measured by RT-PCR and Western Blot analysis.
In the experiments in vitro,we tested the effects on TG and the expressions of apoA5,PPARαand LXRαin HepG2 cells by fructose, fenofibrate and atorvastatin,respectively.Furthermore,we investigated the mechanisms of the three chemicals in regulation of apoA5 expression in cells by treatment with antagonists or inhibitors of PPARαand LXRα.
Ⅱ.Human,animal and cell experiments for APR-induced HTG
1.ACS experiment:
ACS patients(n=228) and healthy volunteers(n=232) were included. After plasma samples obtained,plasma apoAV level was measured by an ELISA method.Besides,plasma lipids and C-reactive protein(CRP) were measured.
2.Acute inflammation experiments:
Thirty two healthy male C57BL/6 mice were randomized into four groups(n=8 each group):(1) control group,with normal diet for four weeks;(2) inflammation group,with normal diet for four weeks and then intraperitoneal injection with 100μg LPS to establish acute inflammatory animal model;(3) statin group,with atorvastatin 10 mg/kg/d for four weeks and then intraperitoneal injection with 100μg LPS;(4) fibrate group,with fenofibrate 100 mg/kg/d for four weeks and then intraperitoneal injection with 100μg LPS.The measurements of fasting plasma lipids and tumor necrosis factor-α(TNFα) were performed at 0 week,4 week before LPS injection,and after LPS injection.The expressions of hepatic gene and protein of apoA5 and PPARαwere measured using RT-PCR and Western Blot analysis respectively.
In the experiments in vitro,we tested the effects on TG and the expressions of apoA5,PPARαand LXRαin HepG2 cells by human recombinant TNFα.Furthermore,we investigated the effects and mechanisms of atorvastatin and fenofibrate on apoA5 expression-induced by TNFα.
Ⅲ.Study for hypertriglyceridemic mechanism for Xuezhikang in CHD patients
1.Trial about lipid-lowering by Xuezhikang:
Sixty stable CAD patients were included,and randomly assigned into two groups to receive 600 mg of xuezhikang(300 mg of cholestin per capsule;WBL Peking University Biotech Co,China) twice daily (xuezhikang group;n = 30) or placebo(placebo group;n = 30) for 6 weeks.Plasma apoAV level was measured by an ELISA method at baseline and six week,and fasting plasma lipids were measured.
2.Animal and cell experiments:
Thirty male Sprague-Dawley rats were randomized into five groups (n=8 each group):(1) control group,with no special treatment;(2) hypertriglyceridemia(HTG) group,with 10%fructose water for two weeks to establish animal HTG model,and with 10%fructose water for next four weeks;(3) low-dose Xuezhikang(L-XZK) group,with 10% fructose water for two weeks and supplemented with Xuezhikang 20 mg/kg/d for next four weeks;(4) high-dose Xuezhikang(H-XZK) group, with 10%fructose water for two weeks and supplemented with Xuezhikang 40 mg/kg/d for next four weeks.The measurements of fasting plasma lipids in rats were performed at 0,2 and 6 week.Liver samples were obtained at 6 week.The gene and protein expressions of hepatic apoA5,PPARαand LXRαwere measured using RT-PCR and WB analysis,respectively.
In the experiments in vitro,we tested the mechanism underlying the effects on TG and the expressions of apoA5,PPARαand LXRαin HepG2 cells by Xuezhikang.
Ⅳ.Human,animal and cell experiments for HTG in MS
1.MS experiment:
MS patients(n=340) and healthy volunteers(n=342) were included. After plasma samples obtained,plasma apoAV level was measured by an ELISA method.Besides,fasting plasma lipids,glucose and insulin were measured.Furthermore,homeostasis model assessment of insulin resistance(HOMA-IR) was calculated.
2.Animal and cell experiments:
Tweenty-four male Sprague-Dawley rats were randomized into three groups(n=8 each group):(1) control group,with no special treatment;(2) MS group,with high- fructose diet(containing 60%fructose) for seven weeks to establish animal MS model;(3) fibrate group,with high-fructose diet and fenofibrate 100 mg/kg/d for seven weeks.The measurements of fasting plasma lipids and tail arterial blood pressure in rats were performed at 0 and 7 week.Then,insulin sensitivity in rats was tested by hyperinsulinemic euglycemic glucose clamp.At the end of study,Liver samples were obtained.The expressions of hepatic apoA5 gene and protein were measured using RT-PCR and Western Blot analysis, respectively.
In the experiments in vitro,we established an insulin resistant hepatocyte model by adding high-dose insulin into HepG2 cells.Then, we tested the effects on TG and apoA5 expression in cells during insulin resistance(IR).Furthermore,we investigated the effect and mechanism of fenofibrate on apoA5 expression in cells during IR.
Results:
Ⅰ.Animal and cell experiments for fructose-induced HTG
1.At 6 week,plasma TG was higher in rats in HTG group,but lower in three drug groups with ascending order as follows: statin＜fibrate＜combination(P＜0.05);However,the expression of hepatic apoA5 gene and protein displayed otherwise.HTG group had lower apoA5 gene and protein,but apoA5 expression increased in three drug groups with ascending order as follows: statin＜fibrate＜combination(P＜0.05).Likewise,fructose decreased apoA5 expression in HepG2 cells,which had been reversed by statin and/or fibrate with ascending order as follows: statin＜fibrate＜combination(P＜0.05).
2.Hepatic PPARαgene decreased in HTG group,and otherwise in three drug groups with ascending order as follows: statin＜fibrate＜combination(P＜0.05),but no signifcant changes were shown in PPARαprotein expression among all groups.Besides, fructose decreased PPARαgene and protein expression in HepG2 cells,which had been reversed by statin and/or fibrate with ascending order as follows:statin＜fibrate＜combination(P＜0.05).
3.Hepatic LXRαgene increased in HTG group and fibrate group,but otherwise in statin group and combination group(P＜0.01).However, there was no significant difference in LXRαprotein expression among all groups.Additionally,fructose and fibrate increased LXRαgene and protein expression in HepG2 cells,and otherwise by treatment of statin(P＜0.01).However,no significant difference in LXRαexpression was seen between combination treatment and control.
Ⅱ.Human,animal and cell experiments for APR-induced HTG
1.Compared with controls,ACS patients had higher plasma apoA5,TG and CRP(P＜0.05).
2.In ACS patients,plasma apoA5 level was positively correlated with TG(r=0.642,P＜0.001) and CRP(r=0.594,P＜0.001),and TG was also positively correlated with CRP(r=0.572,P＜0.001).
3.Multiple logistic regression analysis indicated that plasma apoA5 level may be a protective factor for ACS(OR=0.82,95%CI 0.70-0.95,P=0.02).
4.After LPS injection,plasma TG was obviously higher in mice,but TC,HDL-C and LDL-C was sharply reduced(P＜0.001).However, the magnitude of above lipid changes induced by LPS had been reduced by statin and fibrate(P＜0.05).
5.After LPS injection,the expressions of apoA5 gene and protein obviously increased in mice,but PPARαexpression was significantly impressed(P＜0.05).Likewise,statin and fibrate attenuated the change magnitude of apoA5 and PPARαexpressions induced by LPS (P＜0.05).
6.The treatment of TNFαinduced an elevation of TG in HepG2 cells (P＜0.001),which had been reversed by statin and fibrate(P＜0.05).
7.TNFαconsiderably increased the expressions of apoA5 gene and protein in HepG2 cells,but otherwise for PPARαexpression. Conversely,statin and fibrate can attenuated apoA5 upregulation and PPARαdownregulation by TNFα(P＜0.05).
Ⅲ.Study for hypertriglyceridemic mechanism for Xuezhikang in CHD patients
1.After Xuezhikang therapy,CHD patients had lower plasma TG and higher apoA5 than baseline(P＜0.001).Plasma apoA5 level was significantly inversely correlated with TG in all patients(P＜0.001)
2.Xuezhikang dose-dependently increased hepatic expressions of apoA5 gene and protein,and decreased plasma TG level in rats. Furthermore,Xuezhikang dose-dependently increased hepatic PPARαgene expression,but impressed LXRαgene expression(all P＜0.05).
3.The treatment of Xuezhikang induced an elevation of apoA5 gene and protein in HepG2 cells,resulting in cell TG reduction(P＜0.01). However,the apoA5 upregulation by Xuezhikang had been obviously attenuated by PPARαinhibitor or LXRαagonist(all P＜0.05).
Ⅳ.Human,animal and cell experiments for HTG in MS
1.Compared with controls,MS patients had lower plasma apoA5 and higher TG levels(P＜0.05).An inverse correlation was observed between apoA5 and TG(P＜0.05).Besides,HOMA-IR markedly elevated in MS patients and was negatively related to plasma apoA5 level(P＜0.05).
2.Multiple logistic regression analysis indicated that plasma apoA5 level may be a protective factor for MS(OR=0.77,95%CI0.64-0.92, P=0.04).
3.Compared with controls,MS rats had obviously attenuated insulin sensitivity,higher plasma TG,and reduced expressions of hepatic apoA5 gene and protein(all P＜0.05).
4.After fenofibrate treatment,MS rats had considerably improved insulin sensitivity,reduced plasma TG,and up-regulated expressions of hepatic apoA5 gene and protein(all P＜0.05).
5.By treatment with high-dose insulin,the expressions of apoA5 gene and protein obviously decreased in HepG2 cells,but cellular TG significantly increased.Conversely,the above changes of cell apoA5 and TG by high-dose insulin was effectively reversed by fenofibrate, that was obviously attenuated by a PPARαinhibitor(all P＜0.05).
Conclusions:
1.Fructose inhibits hepatic apoA5 expression by PPARαinhibition and LXRαinduction,resulting in HTG.Fenofibrate and atorvastatin can upregulate apoA5 expression for the treatment of HTG induced by fructose,and a mechanic compensation exists in regulation of apoA5 expression for the two agents.
2.APR increases plasma TG and apoA5.But the elevation of apoA5 may be a compensation for APR,which could not be influenced by PPARαimpression.Fenofibrate and atorvastatin can ameliorate HTG induced by acute inflammation,which is not mainly dependent on apoA5 but is associated with their anti- inflammatory effects.
3.Xuezhikang decreases plasma TG by pregulation of apoA5 expression, which results from PPARαupregulation and LXRαinhibition by this agent.
4.During MS,hepatic expression and plasma level of apoA5 are lower resulting in higher plasma TG level,which could increase MS risk.
5.Fenofibrate decreases plasma TG level in MS rats by upregulation of hepatic apoA5 expression and improvement of IR.
血浆甘油三酯(TG)升高是冠心病的独立危险因素,引起高甘油三酯血症(HTG)常见原因包括高果糖饮食、急性期反应(APR)、代谢综合征(MS)等。降低TG可有效防止冠心病,目前可降低TG的降脂药物主要有:他汀类、贝特类和血脂康等。
载脂蛋白A5(ApoA5)是新发现的载脂蛋白超家族成员,大量研究均证实,ApoA5可显著降低血浆TG。过氧化物酶体增殖物激活受体-α(PPARα)和肝X受体-α(LXRα)是调节ApoA5表达的两个关键核受体,其中,前者上调ApoA5表达,而后者下调ApoA5表达。
然而,目前尚不清楚高果糖饮食、急性期反应以及代谢综合征诱导的HTG是否与ApoA5有关;也不知他汀类、贝特类或血脂康降低TG是否通过ApoA5而起作用。
目的:
明确高果糖饮食、急性期反应以及代谢综合征诱导的HTG是否与ApoA5有关,明确非诺贝特、阿托伐他汀和血脂康降TG作用是否与调节ApoA5有关,并探讨核受体PPARα和LXRα对ApoA5表达的调节作用。
方法:
一.果糖诱导性高甘油三血症的动物和体外实验
40只健康雄性Sprague-Dawley大鼠,随机分为五组(n=8/组):(1)对照组:正常普通饮食喂养;(2)HTG组:10%果糖水喂养2周建立高HTG大鼠模型,并继续喂养4周;(3)贝特组:HTG大鼠建模后,加予非诺贝特(100 mg/kg/天)干预4周;(4)他汀组:HTG大鼠建模后,加予阿托伐他汀(10 mg/kg/天)干预4周;(5)联合组:HTG大鼠建模后,加予非诺贝特(100 mg/kg/天)和阿托伐他汀(10mg/kg/天)干预4周。分别在0周、2周及6周测定体重和空腹血脂。6周后取动物肝脏组织标本,采用免疫组化、逆转录多聚酶链式反应(RT-PCR)及免疫印迹(WB)测定肝脏ApoA5的基因和蛋白表达,同时采用RT-PCR和WB测定肝脏PPARα和LXRα的基因和蛋白表达。
以HepG2细胞为模型,观察果糖、非诺贝特和阿托伐他汀干预后,细胞TG浓度变化,ApoA5、PPARα和LXRα表达的改变,并通过PPARα或LXRα的激动剂或抑制剂干预,揭示三者调控ApoA5表达的机制。
二.急性期反应性高甘油三酯血症的临床、动物及体外实验
(一)ACS临床试验
入选228例ACS患者和232名健康者作为研究对象,抽血分离血浆,采用酶联免疫吸附检测(ELISA)测定ApoA5血浆浓度,同时测定血浆C-反应蛋白和血脂水平。
(二)急性炎症动物和体外实验
32只6周龄健康雌性C57BL/6鼠,随机分为4组(n=8/组):(1)对照组,普通饮食喂养;(2)炎症组,普通饮食喂养4周后,腹腔注射100μg脂多糖(LPS)以建立急性炎症模型;(3)他汀组:阿托伐他汀(10 mg/kg/天)干预4周后,腹腔注射LPS;(4)贝特组,非诺贝特(100 mg/kg/天)干预4周后,腹腔注射LPS。分别在实验第0周、第4周注射LPS前、以及注射LPS后测定空腹血脂和肿瘤坏死因子-α(TNFα)血浆水平。注射LPS后取动物肝脏组织标本,采用RT-PCR和WB测定肝脏ApoA5和PPARα的基因和蛋白表达。
体外观察人重组TNFα对HepG2细胞TG及ApoA5和PPARα表达的影响,同时观察阿托伐他汀和非诺贝特对TNFα刺激下肝细胞ApoA5表达的影响及其机制。
三.血脂康降低冠心病患者甘油三酯的机制研究
(一)血脂康降脂临床试验
入选60例稳定性冠心病患者,随机分为两组,即血脂康组和对照组,分别接受血脂康(600 mg/次,一天两次)和安慰剂治疗,疗程共6周。实验前和实验第6周,采用ELISA测定血浆ApoA5浓度,同时测定空腹血脂水平。
(二)动物和细胞实验
32只健康雄性Sprague-Dawley大鼠,随机分为四组(n=8/组):(1)对照组:正常普通饮食喂养;(2)高甘油三酯血脂(HTG)组:10%果糖水喂养2周建立HTG大鼠模型,并继续喂养4周;(3)血脂康低剂量(L-XZK)组,10%果糖水喂养2周建立HTG大鼠模型后,加予血脂康20 mg/kg/天进行药物干预,干预4周;(4)血脂康高剂量(H-XZK)组,建立HTG大鼠模型后,加予血脂康40 mg/kg/天进行药物干预,干预4周。分别在实验前(0周)、实验后2周及6周测定空腹血脂水平。分别采用RT-PCR和WB测定肝脏ApoA5、PPARα和LXRα的基因和蛋白表达。
体外观察血脂康干预对HepG2细胞TG、以及ApoA5、PPARα和LXRα表达的影响及其机制。
四.代谢综合征临床、动物及体外实验
(一)代谢综合征临床试验
入选340例代谢综合征(MS)患者和342名健康者作为研究对象,采用ELISA测定ApoA5血浆浓度,同时测定空腹血脂、血糖和胰岛素,计算胰岛素抵抗指数(HOMA-IR)。
(二)动物和细胞实验
24只8周龄的健康雄性Sprague-Dawley大鼠,随机分为3组(n=8/组):(1)对照组:普通饮食;(2)MS组:高果糖饮食(含60%果糖),喂养7周;(3)贝特组:高果糖饮食加予非诺贝特100mg/kg/天,干预7周。分别在实验第0周和第7周测定空腹血脂和尾动脉血压,并通过高胰岛素正常血糖钳夹技术测定胰岛素敏感性。实验结束时,取动物肝脏组织标本,采用RT-PCR和WB测定肝脏ApoA5的基因和蛋白表达。
通过高浓度胰岛素诱导HepG2细胞,构建胰岛素抵抗(IR)肝细胞模型,体外观察胰岛素抵抗状况下肝细胞的ApoA5表达和TG变化,探讨非诺贝特对IR状况下肝细胞ApoA5表达的影响及其机制。
结果:
一.果糖诱导性高甘油三酯血症动物和体外实验结果
1.6周后,HTG组大鼠血浆TG显著升高,而药物治疗组TG均显著降低,降低程度依次为:他汀组＜贝特组＜联合组(P＜0.05);相反,HTG组大鼠ApoA5基因和蛋白表达显著降低,而药物治疗组ApoA5表达均显著升高,升高程度依次为:他汀组＜贝特组＜联合组(P＜0.05);与动物实验一致,果糖显著抑制HepG2细胞的ApoA5基因和蛋白表达、升高细胞TG,而药物干预可上调ApoA5表达,降低TG,且疗效显著程度依次为:他汀组＜贝特组＜联合组(P＜0.05)。
2.HTG组大鼠肝脏PPARα基因表达显著下调,而药物治疗组PPARα基因表达显著升高,升高程度依次为:他汀组＜贝特组＜联合组(P＜0.05),但各组大鼠PPARα蛋白表达无显著差异;果糖显著抑制细胞PPARα基因和蛋白表达,而药物干预可上调PPARα基因和蛋白表达,且疗效显著程度依次为:他汀组＜贝特组＜联合组(P＜0.05)。
3.HTG组和贝特组大鼠肝脏LXRα基因表达显著升高,而他汀组LXRα基因表达显著降低(P＜0.01),联合组LXRα基因表达与对照组无显著差异,但各组LXRα蛋白表达无显著差异;果糖和贝特均可上调LXRα基因和蛋白表达,而他汀抑制LXRα表达,联合组LXRα表达与对照组无显著差异。
二.急性期反应性高甘油三血症临床、动物及体外实验结果
1.与对照组比较,ACS患者ApoA5、TG和CRP显著升高(P＜0.05)。
2.ACS患者血浆ApoA5与TG(r=0.642,P＜0.001)和CRP(r=0.594,p＜0.001)均呈显著正相关,且其TG与CRP(r=0.572,P＜0.01)显著正相关。
3.多元Logistic分析显示ApoA5血浆水平可能是ACS保护因素(OR=0.82,95%CI 0.70-0.95,P=0.02)。
4.注射LPS后,炎症组小鼠TG显著升高,而TC、HDL-C和LDL-C显著降低(P＜0.001);而他汀和贝特减轻了炎症引起的上述血脂变化幅度(P＜0.05)。
5.注射LPS后,炎症组小鼠肝脏ApoA5基因和蛋白表达显著升高,而PPARα基因和蛋白表达显著下降(P＜0.01);同样,他汀和贝特减轻了炎症引起的ApoA5和PPARα表达变化幅度(P＜0.05)。
6.TNFα刺激后,HepG2细胞TG显著升高(P＜0.001),而他汀和贝特可以改善TNFα引起的细胞TG升高(P＜0.05)。
7.TNFα刺激可上调HepG2细胞ApoA5基因和蛋白表达,但却抑制PPARα基因和蛋白表达;相反,他汀和贝特一方面可减少TNFα引起的ApoA5表达上调,另一方面可逆转TNFα引起的PPARα表达下降P＜0.05)。
三.血脂康降低冠心病患者甘油三酯的机制研究结果
1.血脂康治疗后,冠心病患者血浆TG显著下降,而ApoA5显著升高;所有冠心病患者ApoA5和TG显著负相关(P＜0.001)。
2.血脂康剂量依赖性升高大鼠肝脏ApoA5基因和蛋白表达,降低血浆TG;血脂康剂量依赖性升高大鼠肝脏PPARα基因表达,抑制LXRα基因表达(P＜0.05)。
3.血脂康显著升高HepG2细胞的ApoA5基因和蛋白表达,降低细胞TG(P＜0.01);PPARα抑制剂或LXRα激动剂显著抑制血脂康上调ApoA5表达作用(P＜0.05)。
四.代谢综合征临床、动物及体外实验
1.与对照组比较,MS患者血浆ApoA5显著降低、TG显著升高,且二者显著负相关(P＜0.05);MS患者HOMA-IR显著升高,且与ApoA5显著负相关(P＜0.05)。
2.多元Logistic分析显示ApoA5血浆水平可能是MS保护因素(OR=0.77,95%CI 0.64-0.92,P=0.04)。
3.与对照组比较,MS大鼠胰岛素敏感性显著下降,而肝脏ApoA5基因和蛋白表达显著下降(P均＜0.05)。
4.非诺贝特干预后,MS大鼠胰岛素敏感性明显增加,TG显著下降,而肝脏ApoA5基因和蛋白表达显著升高(P均＜0.05)。
5.高浓度胰岛素诱导下,HepG2细胞ApoA5基因和蛋白表达显著下降,而TG显著升高;非诺贝特可有效逆转高浓度胰岛素所导致的细胞ApoA5表达下调,降低TG,但加入PPARα抑制剂后,非诺贝特的上述治疗作用丧失(P均＜0.05)。
结论:
1.果糖通过抑制PPARα并上调LXRα表达,抑制肝脏ApoA5表达,诱导HTG;非诺贝特和阿托伐他汀均通过上调ApoA5表达,治疗果糖诱导性HTG,且二者在ApoA5表达调控上存在机制互补性。
2.急性期反应可升高血浆TG,此时ApoA5也显著升高,但可能是机体的一种代偿,与此时PPARα表达下调关系不大;非诺贝特和阿托伐他汀均能降低急性炎症所致TG升高,但该作用不完全通过ApoA5途径,而与二者抗炎作用有关。
3.血脂康通过上调PPARα并抑制LXRα表达,升高ApoA5肝脏表达和血浆水平,降低TG。
4.MS时,ApoA5肝脏表达和血浆水平降低,导致TG升高,增加MS风险;非诺贝特通过升高ApoA5、改善IR,降低MS大鼠血浆TG。
Background:
Elevated plasma triglyceride(TG) is an independent risk factor of coronary heart disease.The common causes for hypertriglyceridemia (HTG) include high fructose diet,acute phase response(APR) and metabolic syndrome(MS).Plasma TG reduction will help to prevent coronary heart disease.
Therefore,it will help to reduce the morbidity and mortality of coronary heart disease by the treatment of high fructose diet-induced HTG.However,the underlying mechanism for high fructose diet-induced HTG remains to be clarified.Fibrate,statin and Xuezhikang are three clinically widely-used hypotriglyceridemic agents.
The recently identified apolipoprotein A5(apoA5) is implicated in TG-lowering by the considerable body of data.Peroxisome proliferator-activated receptor-α(PPARα) and liver X receptor-α(LXRα) are two key nuclear receptors in regulation of apoA5 expression.PPARαcan upregulate apoA5 expression but otherwise for LXRα.
However,it is unclear for the role of apoA5 in HTG induced by high fructose diet,APR and MS.Furthermore,it remains unknown the association of apoA5 with the hypotriglyceridemic effects of fibrate, statin and Xuezhikang.
Objective:
The aim of this study was to define the role of apoA5 in HTG induced by high fructose diet,APR and MS;to investigate the association of apoA5 with the hypotriglyceridemic effects of fibrate,statin and Xuezhikang;to determine the involvement of PPARαand LXRα.
Methods:
Ⅰ.Animal and cell experiments for fructose-induced HTG
Forty healthy male Sprague-Dawley rats were randomized into five groups(n=8 each group):(1) control group,with no special treatment;(2) fructose group,with 10%fructose water for two weeks to establish animal HTG model,and with 10%fructose water for next four weeks;(3) fibrate group,with 10%fructose water for two weeks and supplemented with fenofibrate 100 mg/kg/d for next four weeks;(4) statin group,with 10%fructose water for two weeks and supplemented with atorvastatin 10 mg/kg/d for next four weeks;and(5) combination group,with 10% fructose water for two weeks and supplemented with fenofibrate 100 mg/kg/d and atorvastatin 10 mg/kg/d for next four weeks.The measurements were performed at 0,2 and 6 week for weight and fasting plasma lipids,blood sugar and insulin in animals.Liver samples were obtained at 6 week.The expressions of hepatic apoA5 gene and protein were measured using immunohistochemistry,RT-PCR and Western Blot analysis respectively.Besides,hepatic expressions of PPARαand LXRα were measured by RT-PCR and Western Blot analysis.
In the experiments in vitro,we tested the effects on TG and the expressions of apoA5,PPARαand LXRαin HepG2 cells by fructose, fenofibrate and atorvastatin,respectively.Furthermore,we investigated the mechanisms of the three chemicals in regulation of apoA5 expression in cells by treatment with antagonists or inhibitors of PPARαand LXRα.
Ⅱ.Human,animal and cell experiments for APR-induced HTG
1.ACS experiment:
ACS patients(n=228) and healthy volunteers(n=232) were included. After plasma samples obtained,plasma apoAV level was measured by an ELISA method.Besides,plasma lipids and C-reactive protein(CRP) were measured.
2.Acute inflammation experiments:
Thirty two healthy male C57BL/6 mice were randomized into four groups(n=8 each group):(1) control group,with normal diet for four weeks;(2) inflammation group,with normal diet for four weeks and then intraperitoneal injection with 100μg LPS to establish acute inflammatory animal model;(3) statin group,with atorvastatin 10 mg/kg/d for four weeks and then intraperitoneal injection with 100μg LPS;(4) fibrate group,with fenofibrate 100 mg/kg/d for four weeks and then intraperitoneal injection with 100μg LPS.The measurements of fasting plasma lipids and tumor necrosis factor-α(TNFα) were performed at 0 week,4 week before LPS injection,and after LPS injection.The expressions of hepatic gene and protein of apoA5 and PPARαwere measured using RT-PCR and Western Blot analysis respectively.
In the experiments in vitro,we tested the effects on TG and the expressions of apoA5,PPARαand LXRαin HepG2 cells by human recombinant TNFα.Furthermore,we investigated the effects and mechanisms of atorvastatin and fenofibrate on apoA5 expression-induced by TNFα.
Ⅲ.Study for hypertriglyceridemic mechanism for Xuezhikang in CHD patients
1.Trial about lipid-lowering by Xuezhikang:
Sixty stable CAD patients were included,and randomly assigned into two groups to receive 600 mg of xuezhikang(300 mg of cholestin per capsule;WBL Peking University Biotech Co,China) twice daily (xuezhikang group;n = 30) or placebo(placebo group;n = 30) for 6 weeks.Plasma apoAV level was measured by an ELISA method at baseline and six week,and fasting plasma lipids were measured.
2.Animal and cell experiments:
Thirty male Sprague-Dawley rats were randomized into five groups (n=8 each group):(1) control group,with no special treatment;(2) hypertriglyceridemia(HTG) group,with 10%fructose water for two weeks to establish animal HTG model,and with 10%fructose water for next four weeks;(3) low-dose Xuezhikang(L-XZK) group,with 10% fructose water for two weeks and supplemented with Xuezhikang 20 mg/kg/d for next four weeks;(4) high-dose Xuezhikang(H-XZK) group, with 10%fructose water for two weeks and supplemented with Xuezhikang 40 mg/kg/d for next four weeks.The measurements of fasting plasma lipids in rats were performed at 0,2 and 6 week.Liver samples were obtained at 6 week.The gene and protein expressions of hepatic apoA5,PPARαand LXRαwere measured using RT-PCR and WB analysis,respectively.
In the experiments in vitro,we tested the mechanism underlying the effects on TG and the expressions of apoA5,PPARαand LXRαin HepG2 cells by Xuezhikang.
Ⅳ.Human,animal and cell experiments for HTG in MS
1.MS experiment:
MS patients(n=340) and healthy volunteers(n=342) were included. After plasma samples obtained,plasma apoAV level was measured by an ELISA method.Besides,fasting plasma lipids,glucose and insulin were measured.Furthermore,homeostasis model assessment of insulin resistance(HOMA-IR) was calculated.
2.Animal and cell experiments:
Tweenty-four male Sprague-Dawley rats were randomized into three groups(n=8 each group):(1) control group,with no special treatment;(2) MS group,with high- fructose diet(containing 60%fructose) for seven weeks to establish animal MS model;(3) fibrate group,with high-fructose diet and fenofibrate 100 mg/kg/d for seven weeks.The measurements of fasting plasma lipids and tail arterial blood pressure in rats were performed at 0 and 7 week.Then,insulin sensitivity in rats was tested by hyperinsulinemic euglycemic glucose clamp.At the end of study,Liver samples were obtained.The expressions of hepatic apoA5 gene and protein were measured using RT-PCR and Western Blot analysis, respectively.
In the experiments in vitro,we established an insulin resistant hepatocyte model by adding high-dose insulin into HepG2 cells.Then, we tested the effects on TG and apoA5 expression in cells during insulin resistance(IR).Furthermore,we investigated the effect and mechanism of fenofibrate on apoA5 expression in cells during IR.
Results:
Ⅰ.Animal and cell experiments for fructose-induced HTG
1.At 6 week,plasma TG was higher in rats in HTG group,but lower in three drug groups with ascending order as follows: statin＜fibrate＜combination(P＜0.05);However,the expression of hepatic apoA5 gene and protein displayed otherwise.HTG group had lower apoA5 gene and protein,but apoA5 expression increased in three drug groups with ascending order as follows: statin＜fibrate＜combination(P＜0.05).Likewise,fructose decreased apoA5 expression in HepG2 cells,which had been reversed by statin and/or fibrate with ascending order as follows: statin＜fibrate＜combination(P＜0.05).
2.Hepatic PPARαgene decreased in HTG group,and otherwise in three drug groups with ascending order as follows: statin＜fibrate＜combination(P＜0.05),but no signifcant changes were shown in PPARαprotein expression among all groups.Besides, fructose decreased PPARαgene and protein expression in HepG2 cells,which had been reversed by statin and/or fibrate with ascending order as follows:statin＜fibrate＜combination(P＜0.05).
3.Hepatic LXRαgene increased in HTG group and fibrate group,but otherwise in statin group and combination group(P＜0.01).However, there was no significant difference in LXRαprotein expression among all groups.Additionally,fructose and fibrate increased LXRαgene and protein expression in HepG2 cells,and otherwise by treatment of statin(P＜0.01).However,no significant difference in LXRαexpression was seen between combination treatment and control.
Ⅱ.Human,animal and cell experiments for APR-induced HTG
1.Compared with controls,ACS patients had higher plasma apoA5,TG and CRP(P＜0.05).
2.In ACS patients,plasma apoA5 level was positively correlated with TG(r=0.642,P＜0.001) and CRP(r=0.594,P＜0.001),and TG was also positively correlated with CRP(r=0.572,P＜0.001).
3.Multiple logistic regression analysis indicated that plasma apoA5 level may be a protective factor for ACS(OR=0.82,95%CI 0.70-0.95,P=0.02).
4.After LPS injection,plasma TG was obviously higher in mice,but TC,HDL-C and LDL-C was sharply reduced(P＜0.001).However, the magnitude of above lipid changes induced by LPS had been reduced by statin and fibrate(P＜0.05).
5.After LPS injection,the expressions of apoA5 gene and protein obviously increased in mice,but PPARαexpression was significantly impressed(P＜0.05).Likewise,statin and fibrate attenuated the change magnitude of apoA5 and PPARαexpressions induced by LPS (P＜0.05).
6.The treatment of TNFαinduced an elevation of TG in HepG2 cells (P＜0.001),which had been reversed by statin and fibrate(P＜0.05).
7.TNFαconsiderably increased the expressions of apoA5 gene and protein in HepG2 cells,but otherwise for PPARαexpression. Conversely,statin and fibrate can attenuated apoA5 upregulation and PPARαdownregulation by TNFα(P＜0.05).
Ⅲ.Study for hypertriglyceridemic mechanism for Xuezhikang in CHD patients
1.After Xuezhikang therapy,CHD patients had lower plasma TG and higher apoA5 than baseline(P＜0.001).Plasma apoA5 level was significantly inversely correlated with TG in all patients(P＜0.001)
2.Xuezhikang dose-dependently increased hepatic expressions of apoA5 gene and protein,and decreased plasma TG level in rats. Furthermore,Xuezhikang dose-dependently increased hepatic PPARαgene expression,but impressed LXRαgene expression(all P＜0.05).
3.The treatment of Xuezhikang induced an elevation of apoA5 gene and protein in HepG2 cells,resulting in cell TG reduction(P＜0.01). However,the apoA5 upregulation by Xuezhikang had been obviously attenuated by PPARαinhibitor or LXRαagonist(all P＜0.05).
Ⅳ.Human,animal and cell experiments for HTG in MS
1.Compared with controls,MS patients had lower plasma apoA5 and higher TG levels(P＜0.05).An inverse correlation was observed between apoA5 and TG(P＜0.05).Besides,HOMA-IR markedly elevated in MS patients and was negatively related to plasma apoA5 level(P＜0.05).
2.Multiple logistic regression analysis indicated that plasma apoA5 level may be a protective factor for MS(OR=0.77,95%CI0.64-0.92, P=0.04).
3.Compared with controls,MS rats had obviously attenuated insulin sensitivity,higher plasma TG,and reduced expressions of hepatic apoA5 gene and protein(all P＜0.05).
4.After fenofibrate treatment,MS rats had considerably improved insulin sensitivity,reduced plasma TG,and up-regulated expressions of hepatic apoA5 gene and protein(all P＜0.05).
5.By treatment with high-dose insulin,the expressions of apoA5 gene and protein obviously decreased in HepG2 cells,but cellular TG significantly increased.Conversely,the above changes of cell apoA5 and TG by high-dose insulin was effectively reversed by fenofibrate, that was obviously attenuated by a PPARαinhibitor(all P＜0.05).
Conclusions:
1.Fructose inhibits hepatic apoA5 expression by PPARαinhibition and LXRαinduction,resulting in HTG.Fenofibrate and atorvastatin can upregulate apoA5 expression for the treatment of HTG induced by fructose,and a mechanic compensation exists in regulation of apoA5 expression for the two agents.
2.APR increases plasma TG and apoA5.But the elevation of apoA5 may be a compensation for APR,which could not be influenced by PPARαimpression.Fenofibrate and atorvastatin can ameliorate HTG induced by acute inflammation,which is not mainly dependent on apoA5 but is associated with their anti- inflammatory effects.
3.Xuezhikang decreases plasma TG by pregulation of apoA5 expression, which results from PPARαupregulation and LXRαinhibition by this agent.
4.During MS,hepatic expression and plasma level of apoA5 are lower resulting in higher plasma TG level,which could increase MS risk.
5.Fenofibrate decreases plasma TG level in MS rats by upregulation of hepatic apoA5 expression and improvement of IR.
引文
[1] Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308.
[2] Yuan G, A1-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176:1113-20.
[3] Tounian P, Schneiter P, Henry S, et al. Effects of infused fructose on endogenous glucose production, gluconeogenesis and glycogen metabolism in healthy humans. Am J Physiol Endocrinol Metab. 1994; 267:710-7.
[4] Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001;294:169-73.
[5] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration. J Biol Chem. 2001; 276:44512-20.
[6] Alborn WE, Johnson MG, Prince MJ, et al. Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum. Clin Chem. 2006;52:514-7.
[7] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[8] Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[9] Zhao SP, Hu S, Li J, et al. Association of human serum apolipoprotein A5 with lipid profiles affected by gender. Clin Chim Acta. 2007;376:68-71.
[10]Ishihara M, Kujiraoka T, Iwasaki T, et al. A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration. J Lipid Res. 2005;46:2015-22.
[11]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[12]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278:25468-80.
[13]Jakel H, Nowak M, Moitrot E, et al. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c. J Biol Chem. 2004;279:45462-9.
[14]Kelley GL, Azhar S. Reversal of high dietary fructose-induced PPARalpha suppression by oral administration of lipoxygenase/cyclooxygenase inhibitors. Nutr Metab (Lond). 2005;2:18.
[15]Roglans N, Vila L, Farre M, et al. Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology. 2007;45:778-88.
[16]Mitro N, Mak PA, Vargas L, et al. The nuclear receptor LXR is a glucose sensor. Nature. 2007;445:219-23.
[17]Rizvi F, Puri A, Bhatia G, et al. Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. Biochem Biophys Res Commun. 2003;305:215-22.
[18]Furuhashi M, Ura N, Murakami H, et al. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle. J Endocrinol. 2002; 174:321-9.
[19]Qu S, Su D, Altomonte J, et al. PPARa mediates the hypolipidemic action of fibrates by antagonizing FoxOl. Am J Physiol Endocrinol Metab. 2007;292:E421-34.
[20] Miller AW, Tulbert CD, Busija DW. Rosuvastatin treatment reverses impaired coronary artery vasodilation in fructose-fed, insulin-resistant rats. Am J Physiol Regul Integr Comp Physiol. 2004 Jul;287(l):Rl57-60.
[21] Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest. 2004;114:1564-76.
[22]Roglans N, Sanguino E, Peris C, et al. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Ther. 2002;302:232-9.
[23]Wong J, Quinn CM, Brown AJ. Statins inhibit synthesis of an oxysterol ligand for the liver X receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb VasC Biol. 2004;24:2365-71.
[24]Park J, Lemieux S, Lewis GF, et al. Chronic exogenous insulin and chronic carbohydrate supplementation increase de novo VLDL triglyceride fatty acid production in rats. J Lipid Res. 1997;38:2529-36.
[25]Dorfmeister B, Brandlhofer S, Schaap FG, et al. Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats. Diabetologia. 2006;49:1324-32.
[26]Sanguino E, Roglans N, Alegret M, et al. Atorvastatin reverses age-related reduction in rat hepatic PPARa and HNF-4. Br J Pharmacol. 2005;145:853-61.
[27]Landrier JF, Thomas C, Grober J, et al. Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent. J Biol Chem. 2004;279:45512-8.
[28]Hoekstra M, Kruijt JK, Van Eck M, et al. Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer Cells. J Biol Chem. 2003;278:25448-53.
[29]Russell LE, Harrison WJ, Bahta AW, et al. Characterization of liver X receptor expression and function in human skin and the pilosebaceous unit. Exp Dermatol. 2007;16:844-52.
[30]Havel PJ. Dietary fructose, implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev. 2005;63:133-57.
[31]Schaap FG, Rensen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004;279:27941-7.
[32]Grosskopf I, Baroukh N, Lee SJ, et al. Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vase Biol. 2005;25:2573-9.
[33]Nilsson SK, Lookene A, Beckstead JA, et al. Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family. Biochemistry. 2007;46:3896-904.
[34]Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454:470-7.
[35]Gulick T, Cresci S, Caira T, et al. The peroxisomal proliferator-activated receptor regulates mitochondrial fatty acid oxidative gene expression. Proc Natl Acad Sci U S A. 1994;91:11012-6.
[36]Gebel T, Arand M, Oesch F. Induction of the peroxisome proliferator activated receptor by fenofibrate in rat liver. FEBS Lett. 1992;309:37-40.
[37]Reddy JK, Hashimoto T. Peroxisomal-oxidation and peroxisome proliferator- activated receptor: an adaptive metabolic system. Annu Rev Nutr. 2001;21: 193-230.
[38] Ericsson CG, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996; 347:849-53.
[39]Rizvi F, Puri A, Bhatia G, et al. Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. Biochem Biophys Res Commun. 2003;305:215-22.
[40]Furuhashi M, Ura N, Murakami H, et al. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle. J Endocrinol. 2002; 174:321-9.
[41]Tanabe J, Tamasawa N, Yamashita M, et al. Effects of combined PPARgamma and PPARalpha agonist therapy on reverse cholesterol transport in the Zucker diabetic fatty rat. Diabetes Obes Metab. 2008;10:772-9.
[42]Duez H, Chao YS, Hernandez M, et al. Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. J Biol Chem. 2002;277:48051-7.
[43] Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109-22.
[44]Rosenson RS. Off-target toxicity: risks associated with adrenal corticoid activation in ILLUMINATE. Curr Atheroscler Rep. 2008;10:227-9.
[45] Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-504.
[46]Wierzbicki AS. Atorvastatin. Expert Opin Pharmacother. 2001;2:819-30.
[47] Mangaloglu L, Cheung RC, Van Iderstine SC, et al. Treatment with atorvastatin ameliorates hepatic very-low-density lipoprotein overproduction in an animal model of insulin resistance, the fructose-fed Syrian golden hamster: evidence that reduced hypertriglyceridemia is accompanied by improved hepatic insulin sensitivity. Metabolism. 2002;51:409-18.
[48]Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res. 2007;100:1394-5.
[49] Davidson MH. Clinical significance of statin pleiotropic effects: hypotheses versus evidence. Circulation. 2005;111:2280-1.
[50]Paumelle R, Blanquart C, Briand O, et al. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway. Circ Res. 2006;98:361-9.
[51]Qiu G, Hill JS. Atorvastatin inhibits ABCA1 expression and cholesterol efflux in THP-1 macrophages by an LXR-dependent pathway. J Cardiovasc Pharmacol. 2008;51:388-95.
[52] Wong J, Quinn CM, Gelissen IC, et al. The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation. Atherosclerosis. 2008;196:180-9.
[53]Zanotti I, Poti F, Favari E, et al. Pitavastatin effect on ATP binding cassette A1-mediated lipid efflux from macrophages: evidence for liver X receptor (LXR)-dependent and LXR-independent mechanisms of activation by cAMP. J Pharmacol Exp Then 2006;317:395-401.
[54]Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother. 2001;35:908-17.
[55]Jacobson TA, Zimmerman FH. Fibrates in combination with statins in the management of dyslipidemia. Jacobson TA, Zimmerman FH. J Clin Hypertens (Greenwich). 2006;8:35-41.
[56]Shammas NW, Kapalis MJ, Deckert J, et al. Effectiveness of statin-gemfibrozil combination therapy in patients with mixed hyperlipidemia: experience of a community lipid clinic and safety review from the literature. Prev Cardiol. 2003;6:189-94.
[1] Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448-54.
[2] Khovidhunkit W, Memon RA, Feingold KR, et al. Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis. 2000; 181:S462-72.
[3] Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308.
[4] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-95.
[5] Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724-30.
[6] Esteve E, Ricart W, Fernandez-Real JM. Dyslipidemia and inflammation: an evolutionary conserved mechanism. Clin Nutr. 2005;24:16-31.
[7] Khovidhunkit W, Duchateau PN, Medzihradszky KF, et al. Apolipoproteins A-Ⅳ and A-Ⅴ are acute-phase proteins in mouse HDL. Atherosclerosis. 2004; 176:37-44.
[8] Pitt B, Loscalzo J, Ycas J, et al. Lipid levels after acute coronary syndromes. J Am Coll Cardiol. 2008;51:1440-5.
[9] Becker S, Schomburg L, Renko K, et al. Altered apolipoprotein A-V expression during the acute phase response is independent of plasma triglyceride levels in mice and humans. Biochem Biophys Res Commun. 2006;339:833-9.
[10]Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001 ;294:169-73.
[11] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[12]Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-Ⅴ deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[13]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[14]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278: 25468-80.
[15]Becker J, Delayre-Orthez C, Frossard N, et al. Regulation of peroxisome proliferator-activated receptor-alpha expression during lung inflammation. Pulm Pharmacol Ther. 2008;21:324-30.
[16] Kim MS, Shigenaga J, Moser A, et al. Repression of farnesoid X receptor during the acute phase response. J Biol Chem. 2003;278:8988-95.
[17]Sclia R, Gooszen ME, Jones SP, et al. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation. 2001;103 :2598-603.
[18]Diep QN, Benkirane K, Amiri F, Cohn JS, Endemann D, Schiffrin EL. PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin Ⅱ-infused rats. J Mol Cell Cardiol. 2004;36:295-304.
[19]Roglans N, Sanguino E, Peris C, et al. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Ther. 2002;302:232-9.
[20]Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res. 2007;100:1394-5.
[1] Criqui MH, Heiss G, Cohn R, et al. Plasma triglyceride level and mortality from coronary heart disease. N Engl J Med. 1993;328:1220-5.
[2] Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724-30.
[3] Zhao SP, Liu L, Cheng YC, et al. Xuezhikang, an extract of cholestin, protects endothelial function through antiinflammatory and lipid-lowering mechanisms in patients with coronary heart disease. Circulation. 2004; 110:915-20.
[4] Liu L, Zhao SP, Cheng YC, et al. Xuezhikang decreases serum lipoprotein(a) and C-reactive protein concentrations in patients with coronary heart disease. Clin Chem. 2003; 49:1347-52.
[5] Zhao SP, Liu L, Cheng YC, et al. Effect of xuezhikang, a Cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease. Atherosclerosis. 2003; 168:375-80.
[6] Li JJ, Hu SS, Fang CH, et al. Effects of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with stable angina. Clin Chim Acta. 2005;352:217-24.
[7] Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001 ;294:169-73.
[8] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration. J Biol Chem. 2001; 276:44512-20.
[9] Albom WE, Johnson MG, Prince MJ, et al. Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum. Clin Chem. 2006;52:514-7.
[10] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[11]Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[12]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[13]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278:25468-80.
[14]Jakel H, Nowak M, Moitrot E, et al. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-lc. J Biol Chem. 2004;279:45462-9.
[15] Huang XS, Zhao SP, Bai L, et al. Statin and fibrate synergistically increase apolipoprotein AV and decrease triglycerides through upregulation of PPARa. Br J Pharmacol. 2009 (Accepted)
[16]Park J, Lemieux S, Lewis GF, et al. Chronic exogenous insulin and chronic carbohydrate supplementation increase de novo VLDL triglyceride fatty acid production in rats. J Lipid Res. 1997;38:2529-36.
[17]Dorfmeister B, Brandlhofer S, Schaap FG, et al. Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats. Diabetologia. 2006;49:1324-32.
[18] Schaap FG, Rensen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004;279:27941-7.
[19]Grosskopf I, Baroukh N, Lee SJ, et al. Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vasc Biol. 2005;25:2573-9.
[20]Nilsson SK, Lookene A, Beckstead JA, et al. Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family. Biochemistry. 2007;46:3896-904.
[21]Mansouri RM, Baug(?) E, Gervois P, et al. Atheroprotective effect of human apolipoprotein A5 in a mouse model of mixed dyslipidemia. Circ Res. 2008; 103:450-3.
[22]Roglans N, Sanguino E, Peris C, et al. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Then 2002;302:232-9.
[23]Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res. 2007; 100:1394-5.
[24] Davidson MH. Clinical significance of statin pleiotropic effects: hypotheses versus evidence. Circulation. 2005; 111:2280-1.
[25]Paumelle R, Blanquart C, Briand O, et al. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway. Circ Res. 2006;98:361-9.
[26] Wong J, Quinn CM, Brown AJ. Statins inhibit synthesis of an oxysterol ligand for the liver X receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb Vasc Biol. 2004;24:2365-71.
[27] Sethi S, Ziouzenkova O, Ni H, et al. Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPAR alpha. Blood. 2002;100:1340-6.
[28]Mishra A, Chaudhary A, Sethi S. Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol. 2004;24:1621-7.
[29] Ou J, Tu H, Shan B, et al. Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-lc (SREBP-lc) gene by antagonizing ligand-dependent activation of the LXR. Proc Natl Acad Sci U S A. 2001;98: 6027-32.
[30]Yoshikawa T, Shimano H, Yahagi N, et al. Polyunsaturated fatty acids suppress sterol regulatory element-binding protein lc promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements. J Biol Chem. 2002; 277:1705-11.
[31] Hannah VC, Ou J, Luong A, et al. Unsaturated fatty acids down-regulate SREBP isoforms la and lc by two mechanisms in HEK-293 cells. J Biol Chem. 2001; 276:4365-72.
[32]Kersten S. Effects of fatty acids on gene expression: role of peroxisome proliferator-activated receptor alpha, liver X receptor alpha and sterol regulatory element-binding protein-1c. Proc Nutr Soc. 2002;61:371-4.
[33] Jump DB. Dietary polyunsaturated fatty acids and regulation of gene transcription. Curr Opin Lipidol.2002;13:155-64.
[34]Ukropec J,Reseland JE,Gasperikova D,et al.The hypotriglyceridemic effect of dietary n-3 FA is associated with increased beta-oxidation and reduced leptin expression.Lipids.2003;38:1023-9.
[35]Davidson MH.Mechanisms for the hypotriglyceridemic effect of marine omega-3fatty acids.Am J Cardiol.2006;98:27-33.
[1] Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008;28:629-36.
[2] Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-28.
[3] Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001 ;294:169-73.
[4] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration. J Biol Chem. 2001; 276:44512-20.
[5] Alborn WE, Johnson MG, Prince MJ, et al. Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum. Clin Chem. 2006;52:514-7.
[6] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[7] Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[8] Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[9] Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278:25468-80.
[10]Niculescu LS, Fruchart-Najib J, Fruchart JC, et al. Apolipoprotein A-V gene polymorphisms in subjects with metabolic syndrome. Clin Chem Lab Med. 2007;45:1133-9.
[11]Yamada Y, Kato K, Hibino T, et al. Prediction of genetic risk for metabolic syndrome. Atherosclerosis. 2007;191:298-304.
[12]Maasz A, Kisfali P, Horvatovich K, et al. Apolipoprotein A5 T-1131C variant confers risk for metabolic syndrome.Pathol Oncol Res.2007;13:243-7.
[13]Ericsson CG,Hamsten A,Nilsson J,et al.Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients.Lancet.1996;347:849-53.
[14]Nieuwdorp M,Stroes ES,Kastelein JJ,et al.Normalization of metabolic syndrome using fenofibrate,metformin or their combination.Diabetes Obes Metab.2007;9:869-78.
[15]Kilicarslan A,Yavuz B,Guven GS,et al.Fenofibrate improves endothelial function and decreases thrombin-activatable fibrinolysis inhibitor concentration in metabolic syndrome.Blood Coagul Fibrinolysis.2008;19:310-4.
[16]中国成人血脂异常防治指南制订联合委员会.中国成人血脂异常防治指南.中华心血管病杂志.2007;35(5):390-417.
[17]Oron-Herman M,Kamari Y,Grossman E,et al.Metabolic syndrome:comparison of the two commonly used animal models.Am J Hypertens.2008;21:1018-22.
[18]Xie W,Wang W,Su H,et al.Effect of ethanolic extracts of Ananas comosus L.leaves on insulin sensitivity in rats and HepG2.Comp Biochem Physiol C Toxicol Pharmacol.2006;143:429-35.
[19]Lewis GF,Uffelman KD,Szeto LW,et al.Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.J Clin Invest;1995;95:158-66.
[20]Hsu LA,Ko YL,Chang CJ,et al.Apolipoprotein A5 gene -1131T/C polymorphism is associated with the risk of metabolic syndrome in ethnic Chinese in Taiwan.Clin Chem Lab Med.2008;46:1714-9.
[21]Dallongeville J,Cottel D,Wagner A,et al.The APOA5 Trp19 allele is associated with metabolic syndrome via its association with plasma triglycerides.BMC Med Genet.2008;12;9:84.
[22]Komurcu-Bayrak E,Onat A,Poda M,et al.Gender-modulated impact of apolipoprotein A5 gene(APOA5) -1131T＞C and c.56C＞G polymorphisms on lipids,dyslipidemia and metabolic syndrome in Turkish adults.Clin Chem Lab Med.2008;46:778-84.
[23]Kisfali P,Moh(?)s M,Maasz A,et al.Apolipoprotein A5 ⅣS3+476A allelic variant associates with increased trigliceride levels and confers risk for development of metabolic syndrome in Hungarians.Circ J.2008;72:40-3.
[24]Ma(?)sz A, Kisfali P, Horvatovich K, et al. Apolipoprotein A5 T-1131C variant confers risk for metabolic syndrome. Pathol Oncol Res. 2007;13:243-7.
[25]Yamada Y, Ichihara S, Kato K, et al. Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese people. J Med Genet. 2008;45:22-8.
[26]Lind L, Vessby B, Sundstr(?)m J. The apolipoprotein B/AI ratio and the metabolic syndrome independently predict risk for myocardial infarction in middle-aged men. Arterioscler Thromb Vasc Biol. 2006;26:406-10.
[27]Nowak M, Helleboid-Chapman A, Jakel H, et al. Insulin-mediated down-regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway: role of upstream stimulatory factor. Mol Cell Biol 2005;25:1537-48.
[28] Miranda PJ, DeFronzo RA, Califf RM, et al. Metabolic syndrome: definition, pathophysiology, and mechanisms. Am Heart J 2005; 149:33-45.
[29]Zammit VA, Waterman IJ, Topping D, et al. Insulin stimulation of hepatic triacylglycerol secretion and the etiology of insulin resistance. J Nutr. 2001;131:2074-7.
[30]Cardona F, Guardiola M, Queipo-Ortuno MI, et al. The -1131T>C SNP of the APOA5 gene modulates response to fenofibrate treatment in patients with the metabolic syndrome: A postprandial study. Atherosclerosis. 2009 Mar 11. [Epub ahead of print]
[1]Pennacchio LA,Olivier M,Hubacek JA,et al.An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science.2001;294:169-73.
[2]van der Vliet HN,Sammels MG,Leegwater AC,et al.Apolipoprotein A-V:a novel apolipoprotein associated with an early phase of liver regeneration.J Biol Chem.2001;276:44512-20.
[3]Priore Oliva C,Pisciotta L,Li Volti G,et al.Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia.Arterioscler Thromb Vase Biol.2005; 25:411-7.
[4] O'Brien PJ, AlbornWE, Sloan JH, et al. The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins. Clin Chem. 2005; 51:351-9.
[5] Wong K, Ryan RO. Characterization of apolipoprotein A-V structure and mode of plasma triacylglycerol regulation. Curr Opin Lipidol. 2007;18:319-24.
[6] Beckstead JA, Wong K, Gupta V, et al. The C terminus of apolipoprotein A-V modulates lipid-binding activity. J Biol Chem. 2007;282:15484-9.
[7] Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454:470-7.
[8] Ahmed I, Furlong K, Flood J, et al. Dual PPAR alpha/gamma agonists: promises and pitfalls in type 2 diabetes. Am J Then 2007;14:49-62.
[9] Lefebvre P, Chinetti G, Fruchart JC, et al. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest. 2006;l 16:571-80.
[10]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003;278:17982-5.
[11]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003 ;278: 25468-80.
[12]Guardiola M, Alvaro A, Vallve J.C, et al. Apolipoprotein A5 is expressed in human small intestine and is upregulated by fibrates. Atherosclerosis Supplements. 2007;8:62.
[13]Dorfmeister B, Brandlhofer S, Schaap FG, et al. Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats. Diabetologia. 2006,49:1324-32.
[14]Baranowski M. Biological role of liver X receptors J Physiol Pharmacol. 2008; 59 Suppl 7:31-55.
[15]Jakel H, Nowak M, Moitrot E, et al. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c. J Biol Chem. 2004;279:45462-9.
[16]Stedman C, Liddle C, Coulter S, et al. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci U S A. 2006; 103:11323-8.
[17] Gold DA, Gent PM, Hamilton BA. ROR alpha in genetic control of cerebellum development: 50 staggering years. Brain Res. 2007; 1140:19-25.
[18]Lind U, Nilsson T, McPheat J, et al. Identification of the human ApoAV gene as a novel RORalpha target gene. Biochem Biophys Res Commun. 2005,330:233-41.
[19]Genoux A, Dehondt H, Helleboid-Chapman A, et al. Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORalpha. Arterioscler Thromb Vasc Biol. 2005,25:1186-92.
[20]Hayhurst GP, Lee YH, Lambert G, et al. Hepatocyte nuclear factor 4-a (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol. 2001;21:1393-403.
[21]Tirona RG, Lee W, Leake BF, et al. The orphan nuclear receptor HNF4-a determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med. 2003;9:220-4.
[22]Prieur X, Schaap FG, Coste H, et al. Hepatocyte nuclear factor-4alpha regulates the human apolipoprotein AV gene: identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, AMP-activated protein kinase, and mi to gen-activated protein kinase pathway. Mol Endocrinol. 2005; 19:3107-25.
[23]Ito M, Takamatsu J, Matsuo T, et al. Serum concentrations of remnant-like particles in hypothyroid patients before and after thyroxine replacement. Clin Endocrinol (Oxf). 2003;58:621-6.
[24] Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev. 2001;81:1097-142.
[25]Prieur X, Huby T, Coste H, et al. Thyroid hormone regulates the hypotriglyceridemic gene APOAV. J Biol Chem. 2005;280:27533-43.
[26]Murao K, Wada Y, Nakamura T, et al. Effects of glucose and insulin on rat apolipoprotein A-I gene expression. J Biol Chem. 1998;273:18959-65.
[27] Chen M, Breslow JL, Li W, et al. Transcriptional regulation of the apoC-Ⅲ gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels. J Lipid Res. 1994;35:1918-24.
[28] Evert M, Schneider-Stock R, Dombrowski F. Apolipoprotein A-Ⅳ mRNA overexpression in early preneoplastic hepatic foci induced by low-number pancreatic islet transplants in streptozotocin-diabetic rats. Pathol Res Pract. 2003;199:373-9.
[29] Siri P, Candella N, Ko C, et al. Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B-lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance. J Biol Chem. 2001;276:46064-72.
[30] Yu Y-H, Ginsberg HN. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circ Res. 2005;96:1042-52.
[31]Miyashita Y, Shirai K, Itoh Y, et al. Low lipoprotein lipase mass in preheparin serum of type 2 diabetes mellitus patients and its recovery with insulin therapy. Diabetes Res Clin Pract. 2002;56:181-7.
[32]Nowak M, Helleboid-Chapman A, Jakel H, et al. Insulin-mediated down- regulation of apolipoprotein A5 gene expression through the phosphatidyhnositol 3-kinase pathway: role of upstream stimulatory factor. Mol Cell Biol. 2005;25:1537-48.
[33]Lefrancois-Martinez AM, Martinez A, et al. Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. J Biol Chem. 1995;270:2640-3.
[34]Nowak M, Helleboid-Chapman A, Jakel H, et al. Glucose regulates the expression of the apolipoprotein A5 gene. J Mol Biol. 2008;380:789-98.
[35]Lai CQ, Corella D, Demissie S, et al. Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study. Circulation. 2006; 113:2062-70.
[36]Tai ES, Corella D, Demissie S, et al. Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglycerides and apolipoprotein C3 concentrations in the Framingham Heart Study. J Nutr. 2005;135:397-403.
[2] Yuan G, A1-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176:1113-20.
[3] Tounian P, Schneiter P, Henry S, et al. Effects of infused fructose on endogenous glucose production, gluconeogenesis and glycogen metabolism in healthy humans. Am J Physiol Endocrinol Metab. 1994; 267:710-7.
[4] Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001;294:169-73.
[5] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration. J Biol Chem. 2001; 276:44512-20.
[6] Alborn WE, Johnson MG, Prince MJ, et al. Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum. Clin Chem. 2006;52:514-7.
[7] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[8] Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[9] Zhao SP, Hu S, Li J, et al. Association of human serum apolipoprotein A5 with lipid profiles affected by gender. Clin Chim Acta. 2007;376:68-71.
[10]Ishihara M, Kujiraoka T, Iwasaki T, et al. A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration. J Lipid Res. 2005;46:2015-22.
[11]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[12]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278:25468-80.
[13]Jakel H, Nowak M, Moitrot E, et al. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c. J Biol Chem. 2004;279:45462-9.
[14]Kelley GL, Azhar S. Reversal of high dietary fructose-induced PPARalpha suppression by oral administration of lipoxygenase/cyclooxygenase inhibitors. Nutr Metab (Lond). 2005;2:18.
[15]Roglans N, Vila L, Farre M, et al. Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology. 2007;45:778-88.
[16]Mitro N, Mak PA, Vargas L, et al. The nuclear receptor LXR is a glucose sensor. Nature. 2007;445:219-23.
[17]Rizvi F, Puri A, Bhatia G, et al. Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. Biochem Biophys Res Commun. 2003;305:215-22.
[18]Furuhashi M, Ura N, Murakami H, et al. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle. J Endocrinol. 2002; 174:321-9.
[19]Qu S, Su D, Altomonte J, et al. PPARa mediates the hypolipidemic action of fibrates by antagonizing FoxOl. Am J Physiol Endocrinol Metab. 2007;292:E421-34.
[20] Miller AW, Tulbert CD, Busija DW. Rosuvastatin treatment reverses impaired coronary artery vasodilation in fructose-fed, insulin-resistant rats. Am J Physiol Regul Integr Comp Physiol. 2004 Jul;287(l):Rl57-60.
[21] Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest. 2004;114:1564-76.
[22]Roglans N, Sanguino E, Peris C, et al. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Ther. 2002;302:232-9.
[23]Wong J, Quinn CM, Brown AJ. Statins inhibit synthesis of an oxysterol ligand for the liver X receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb VasC Biol. 2004;24:2365-71.
[24]Park J, Lemieux S, Lewis GF, et al. Chronic exogenous insulin and chronic carbohydrate supplementation increase de novo VLDL triglyceride fatty acid production in rats. J Lipid Res. 1997;38:2529-36.
[25]Dorfmeister B, Brandlhofer S, Schaap FG, et al. Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats. Diabetologia. 2006;49:1324-32.
[26]Sanguino E, Roglans N, Alegret M, et al. Atorvastatin reverses age-related reduction in rat hepatic PPARa and HNF-4. Br J Pharmacol. 2005;145:853-61.
[27]Landrier JF, Thomas C, Grober J, et al. Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent. J Biol Chem. 2004;279:45512-8.
[28]Hoekstra M, Kruijt JK, Van Eck M, et al. Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer Cells. J Biol Chem. 2003;278:25448-53.
[29]Russell LE, Harrison WJ, Bahta AW, et al. Characterization of liver X receptor expression and function in human skin and the pilosebaceous unit. Exp Dermatol. 2007;16:844-52.
[30]Havel PJ. Dietary fructose, implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev. 2005;63:133-57.
[31]Schaap FG, Rensen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004;279:27941-7.
[32]Grosskopf I, Baroukh N, Lee SJ, et al. Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vase Biol. 2005;25:2573-9.
[33]Nilsson SK, Lookene A, Beckstead JA, et al. Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family. Biochemistry. 2007;46:3896-904.
[34]Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454:470-7.
[35]Gulick T, Cresci S, Caira T, et al. The peroxisomal proliferator-activated receptor regulates mitochondrial fatty acid oxidative gene expression. Proc Natl Acad Sci U S A. 1994;91:11012-6.
[36]Gebel T, Arand M, Oesch F. Induction of the peroxisome proliferator activated receptor by fenofibrate in rat liver. FEBS Lett. 1992;309:37-40.
[37]Reddy JK, Hashimoto T. Peroxisomal-oxidation and peroxisome proliferator- activated receptor: an adaptive metabolic system. Annu Rev Nutr. 2001;21: 193-230.
[38] Ericsson CG, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996; 347:849-53.
[39]Rizvi F, Puri A, Bhatia G, et al. Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. Biochem Biophys Res Commun. 2003;305:215-22.
[40]Furuhashi M, Ura N, Murakami H, et al. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle. J Endocrinol. 2002; 174:321-9.
[41]Tanabe J, Tamasawa N, Yamashita M, et al. Effects of combined PPARgamma and PPARalpha agonist therapy on reverse cholesterol transport in the Zucker diabetic fatty rat. Diabetes Obes Metab. 2008;10:772-9.
[42]Duez H, Chao YS, Hernandez M, et al. Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. J Biol Chem. 2002;277:48051-7.
[43] Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109-22.
[44]Rosenson RS. Off-target toxicity: risks associated with adrenal corticoid activation in ILLUMINATE. Curr Atheroscler Rep. 2008;10:227-9.
[45] Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-504.
[46]Wierzbicki AS. Atorvastatin. Expert Opin Pharmacother. 2001;2:819-30.
[47] Mangaloglu L, Cheung RC, Van Iderstine SC, et al. Treatment with atorvastatin ameliorates hepatic very-low-density lipoprotein overproduction in an animal model of insulin resistance, the fructose-fed Syrian golden hamster: evidence that reduced hypertriglyceridemia is accompanied by improved hepatic insulin sensitivity. Metabolism. 2002;51:409-18.
[48]Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res. 2007;100:1394-5.
[49] Davidson MH. Clinical significance of statin pleiotropic effects: hypotheses versus evidence. Circulation. 2005;111:2280-1.
[50]Paumelle R, Blanquart C, Briand O, et al. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway. Circ Res. 2006;98:361-9.
[51]Qiu G, Hill JS. Atorvastatin inhibits ABCA1 expression and cholesterol efflux in THP-1 macrophages by an LXR-dependent pathway. J Cardiovasc Pharmacol. 2008;51:388-95.
[52] Wong J, Quinn CM, Gelissen IC, et al. The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation. Atherosclerosis. 2008;196:180-9.
[53]Zanotti I, Poti F, Favari E, et al. Pitavastatin effect on ATP binding cassette A1-mediated lipid efflux from macrophages: evidence for liver X receptor (LXR)-dependent and LXR-independent mechanisms of activation by cAMP. J Pharmacol Exp Then 2006;317:395-401.
[54]Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother. 2001;35:908-17.
[55]Jacobson TA, Zimmerman FH. Fibrates in combination with statins in the management of dyslipidemia. Jacobson TA, Zimmerman FH. J Clin Hypertens (Greenwich). 2006;8:35-41.
[56]Shammas NW, Kapalis MJ, Deckert J, et al. Effectiveness of statin-gemfibrozil combination therapy in patients with mixed hyperlipidemia: experience of a community lipid clinic and safety review from the literature. Prev Cardiol. 2003;6:189-94.
[1] Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448-54.
[2] Khovidhunkit W, Memon RA, Feingold KR, et al. Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis. 2000; 181:S462-72.
[3] Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308.
[4] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-95.
[5] Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724-30.
[6] Esteve E, Ricart W, Fernandez-Real JM. Dyslipidemia and inflammation: an evolutionary conserved mechanism. Clin Nutr. 2005;24:16-31.
[7] Khovidhunkit W, Duchateau PN, Medzihradszky KF, et al. Apolipoproteins A-Ⅳ and A-Ⅴ are acute-phase proteins in mouse HDL. Atherosclerosis. 2004; 176:37-44.
[8] Pitt B, Loscalzo J, Ycas J, et al. Lipid levels after acute coronary syndromes. J Am Coll Cardiol. 2008;51:1440-5.
[9] Becker S, Schomburg L, Renko K, et al. Altered apolipoprotein A-V expression during the acute phase response is independent of plasma triglyceride levels in mice and humans. Biochem Biophys Res Commun. 2006;339:833-9.
[10]Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001 ;294:169-73.
[11] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[12]Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-Ⅴ deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[13]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[14]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278: 25468-80.
[15]Becker J, Delayre-Orthez C, Frossard N, et al. Regulation of peroxisome proliferator-activated receptor-alpha expression during lung inflammation. Pulm Pharmacol Ther. 2008;21:324-30.
[16] Kim MS, Shigenaga J, Moser A, et al. Repression of farnesoid X receptor during the acute phase response. J Biol Chem. 2003;278:8988-95.
[17]Sclia R, Gooszen ME, Jones SP, et al. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation. 2001;103 :2598-603.
[18]Diep QN, Benkirane K, Amiri F, Cohn JS, Endemann D, Schiffrin EL. PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin Ⅱ-infused rats. J Mol Cell Cardiol. 2004;36:295-304.
[19]Roglans N, Sanguino E, Peris C, et al. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Ther. 2002;302:232-9.
[20]Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res. 2007;100:1394-5.
[1] Criqui MH, Heiss G, Cohn R, et al. Plasma triglyceride level and mortality from coronary heart disease. N Engl J Med. 1993;328:1220-5.
[2] Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724-30.
[3] Zhao SP, Liu L, Cheng YC, et al. Xuezhikang, an extract of cholestin, protects endothelial function through antiinflammatory and lipid-lowering mechanisms in patients with coronary heart disease. Circulation. 2004; 110:915-20.
[4] Liu L, Zhao SP, Cheng YC, et al. Xuezhikang decreases serum lipoprotein(a) and C-reactive protein concentrations in patients with coronary heart disease. Clin Chem. 2003; 49:1347-52.
[5] Zhao SP, Liu L, Cheng YC, et al. Effect of xuezhikang, a Cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease. Atherosclerosis. 2003; 168:375-80.
[6] Li JJ, Hu SS, Fang CH, et al. Effects of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with stable angina. Clin Chim Acta. 2005;352:217-24.
[7] Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001 ;294:169-73.
[8] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration. J Biol Chem. 2001; 276:44512-20.
[9] Albom WE, Johnson MG, Prince MJ, et al. Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum. Clin Chem. 2006;52:514-7.
[10] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[11]Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[12]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[13]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278:25468-80.
[14]Jakel H, Nowak M, Moitrot E, et al. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-lc. J Biol Chem. 2004;279:45462-9.
[15] Huang XS, Zhao SP, Bai L, et al. Statin and fibrate synergistically increase apolipoprotein AV and decrease triglycerides through upregulation of PPARa. Br J Pharmacol. 2009 (Accepted)
[16]Park J, Lemieux S, Lewis GF, et al. Chronic exogenous insulin and chronic carbohydrate supplementation increase de novo VLDL triglyceride fatty acid production in rats. J Lipid Res. 1997;38:2529-36.
[17]Dorfmeister B, Brandlhofer S, Schaap FG, et al. Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats. Diabetologia. 2006;49:1324-32.
[18] Schaap FG, Rensen PC, Voshol PJ, et al. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004;279:27941-7.
[19]Grosskopf I, Baroukh N, Lee SJ, et al. Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vasc Biol. 2005;25:2573-9.
[20]Nilsson SK, Lookene A, Beckstead JA, et al. Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family. Biochemistry. 2007;46:3896-904.
[21]Mansouri RM, Baug(?) E, Gervois P, et al. Atheroprotective effect of human apolipoprotein A5 in a mouse model of mixed dyslipidemia. Circ Res. 2008; 103:450-3.
[22]Roglans N, Sanguino E, Peris C, et al. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Then 2002;302:232-9.
[23]Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res. 2007; 100:1394-5.
[24] Davidson MH. Clinical significance of statin pleiotropic effects: hypotheses versus evidence. Circulation. 2005; 111:2280-1.
[25]Paumelle R, Blanquart C, Briand O, et al. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway. Circ Res. 2006;98:361-9.
[26] Wong J, Quinn CM, Brown AJ. Statins inhibit synthesis of an oxysterol ligand for the liver X receptor in human macrophages with consequences for cholesterol flux. Arterioscler Thromb Vasc Biol. 2004;24:2365-71.
[27] Sethi S, Ziouzenkova O, Ni H, et al. Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPAR alpha. Blood. 2002;100:1340-6.
[28]Mishra A, Chaudhary A, Sethi S. Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway. Arterioscler Thromb Vasc Biol. 2004;24:1621-7.
[29] Ou J, Tu H, Shan B, et al. Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-lc (SREBP-lc) gene by antagonizing ligand-dependent activation of the LXR. Proc Natl Acad Sci U S A. 2001;98: 6027-32.
[30]Yoshikawa T, Shimano H, Yahagi N, et al. Polyunsaturated fatty acids suppress sterol regulatory element-binding protein lc promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements. J Biol Chem. 2002; 277:1705-11.
[31] Hannah VC, Ou J, Luong A, et al. Unsaturated fatty acids down-regulate SREBP isoforms la and lc by two mechanisms in HEK-293 cells. J Biol Chem. 2001; 276:4365-72.
[32]Kersten S. Effects of fatty acids on gene expression: role of peroxisome proliferator-activated receptor alpha, liver X receptor alpha and sterol regulatory element-binding protein-1c. Proc Nutr Soc. 2002;61:371-4.
[33] Jump DB. Dietary polyunsaturated fatty acids and regulation of gene transcription. Curr Opin Lipidol.2002;13:155-64.
[34]Ukropec J,Reseland JE,Gasperikova D,et al.The hypotriglyceridemic effect of dietary n-3 FA is associated with increased beta-oxidation and reduced leptin expression.Lipids.2003;38:1023-9.
[35]Davidson MH.Mechanisms for the hypotriglyceridemic effect of marine omega-3fatty acids.Am J Cardiol.2006;98:27-33.
[1] Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008;28:629-36.
[2] Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-28.
[3] Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001 ;294:169-73.
[4] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration. J Biol Chem. 2001; 276:44512-20.
[5] Alborn WE, Johnson MG, Prince MJ, et al. Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum. Clin Chem. 2006;52:514-7.
[6] van der Vliet HN, Schaap FG, Levels JH, et al. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun. 2002;295:1156-9.
[7] Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411-7.
[8] Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003 ;278:17982-5.
[9] Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003,278:25468-80.
[10]Niculescu LS, Fruchart-Najib J, Fruchart JC, et al. Apolipoprotein A-V gene polymorphisms in subjects with metabolic syndrome. Clin Chem Lab Med. 2007;45:1133-9.
[11]Yamada Y, Kato K, Hibino T, et al. Prediction of genetic risk for metabolic syndrome. Atherosclerosis. 2007;191:298-304.
[12]Maasz A, Kisfali P, Horvatovich K, et al. Apolipoprotein A5 T-1131C variant confers risk for metabolic syndrome.Pathol Oncol Res.2007;13:243-7.
[13]Ericsson CG,Hamsten A,Nilsson J,et al.Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients.Lancet.1996;347:849-53.
[14]Nieuwdorp M,Stroes ES,Kastelein JJ,et al.Normalization of metabolic syndrome using fenofibrate,metformin or their combination.Diabetes Obes Metab.2007;9:869-78.
[15]Kilicarslan A,Yavuz B,Guven GS,et al.Fenofibrate improves endothelial function and decreases thrombin-activatable fibrinolysis inhibitor concentration in metabolic syndrome.Blood Coagul Fibrinolysis.2008;19:310-4.
[16]中国成人血脂异常防治指南制订联合委员会.中国成人血脂异常防治指南.中华心血管病杂志.2007;35(5):390-417.
[17]Oron-Herman M,Kamari Y,Grossman E,et al.Metabolic syndrome:comparison of the two commonly used animal models.Am J Hypertens.2008;21:1018-22.
[18]Xie W,Wang W,Su H,et al.Effect of ethanolic extracts of Ananas comosus L.leaves on insulin sensitivity in rats and HepG2.Comp Biochem Physiol C Toxicol Pharmacol.2006;143:429-35.
[19]Lewis GF,Uffelman KD,Szeto LW,et al.Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.J Clin Invest;1995;95:158-66.
[20]Hsu LA,Ko YL,Chang CJ,et al.Apolipoprotein A5 gene -1131T/C polymorphism is associated with the risk of metabolic syndrome in ethnic Chinese in Taiwan.Clin Chem Lab Med.2008;46:1714-9.
[21]Dallongeville J,Cottel D,Wagner A,et al.The APOA5 Trp19 allele is associated with metabolic syndrome via its association with plasma triglycerides.BMC Med Genet.2008;12;9:84.
[22]Komurcu-Bayrak E,Onat A,Poda M,et al.Gender-modulated impact of apolipoprotein A5 gene(APOA5) -1131T＞C and c.56C＞G polymorphisms on lipids,dyslipidemia and metabolic syndrome in Turkish adults.Clin Chem Lab Med.2008;46:778-84.
[23]Kisfali P,Moh(?)s M,Maasz A,et al.Apolipoprotein A5 ⅣS3+476A allelic variant associates with increased trigliceride levels and confers risk for development of metabolic syndrome in Hungarians.Circ J.2008;72:40-3.
[24]Ma(?)sz A, Kisfali P, Horvatovich K, et al. Apolipoprotein A5 T-1131C variant confers risk for metabolic syndrome. Pathol Oncol Res. 2007;13:243-7.
[25]Yamada Y, Ichihara S, Kato K, et al. Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese people. J Med Genet. 2008;45:22-8.
[26]Lind L, Vessby B, Sundstr(?)m J. The apolipoprotein B/AI ratio and the metabolic syndrome independently predict risk for myocardial infarction in middle-aged men. Arterioscler Thromb Vasc Biol. 2006;26:406-10.
[27]Nowak M, Helleboid-Chapman A, Jakel H, et al. Insulin-mediated down-regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway: role of upstream stimulatory factor. Mol Cell Biol 2005;25:1537-48.
[28] Miranda PJ, DeFronzo RA, Califf RM, et al. Metabolic syndrome: definition, pathophysiology, and mechanisms. Am Heart J 2005; 149:33-45.
[29]Zammit VA, Waterman IJ, Topping D, et al. Insulin stimulation of hepatic triacylglycerol secretion and the etiology of insulin resistance. J Nutr. 2001;131:2074-7.
[30]Cardona F, Guardiola M, Queipo-Ortuno MI, et al. The -1131T>C SNP of the APOA5 gene modulates response to fenofibrate treatment in patients with the metabolic syndrome: A postprandial study. Atherosclerosis. 2009 Mar 11. [Epub ahead of print]
[1]Pennacchio LA,Olivier M,Hubacek JA,et al.An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science.2001;294:169-73.
[2]van der Vliet HN,Sammels MG,Leegwater AC,et al.Apolipoprotein A-V:a novel apolipoprotein associated with an early phase of liver regeneration.J Biol Chem.2001;276:44512-20.
[3]Priore Oliva C,Pisciotta L,Li Volti G,et al.Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia.Arterioscler Thromb Vase Biol.2005; 25:411-7.
[4] O'Brien PJ, AlbornWE, Sloan JH, et al. The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins. Clin Chem. 2005; 51:351-9.
[5] Wong K, Ryan RO. Characterization of apolipoprotein A-V structure and mode of plasma triacylglycerol regulation. Curr Opin Lipidol. 2007;18:319-24.
[6] Beckstead JA, Wong K, Gupta V, et al. The C terminus of apolipoprotein A-V modulates lipid-binding activity. J Biol Chem. 2007;282:15484-9.
[7] Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454:470-7.
[8] Ahmed I, Furlong K, Flood J, et al. Dual PPAR alpha/gamma agonists: promises and pitfalls in type 2 diabetes. Am J Then 2007;14:49-62.
[9] Lefebvre P, Chinetti G, Fruchart JC, et al. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest. 2006;l 16:571-80.
[10]Vu-Dac N, Gervois P, Jakel H, et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator- activated receptor alpha activators. J Biol Chem. 2003;278:17982-5.
[11]Prieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. J Biol Chem. 2003 ;278: 25468-80.
[12]Guardiola M, Alvaro A, Vallve J.C, et al. Apolipoprotein A5 is expressed in human small intestine and is upregulated by fibrates. Atherosclerosis Supplements. 2007;8:62.
[13]Dorfmeister B, Brandlhofer S, Schaap FG, et al. Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats. Diabetologia. 2006,49:1324-32.
[14]Baranowski M. Biological role of liver X receptors J Physiol Pharmacol. 2008; 59 Suppl 7:31-55.
[15]Jakel H, Nowak M, Moitrot E, et al. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c. J Biol Chem. 2004;279:45462-9.
[16]Stedman C, Liddle C, Coulter S, et al. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci U S A. 2006; 103:11323-8.
[17] Gold DA, Gent PM, Hamilton BA. ROR alpha in genetic control of cerebellum development: 50 staggering years. Brain Res. 2007; 1140:19-25.
[18]Lind U, Nilsson T, McPheat J, et al. Identification of the human ApoAV gene as a novel RORalpha target gene. Biochem Biophys Res Commun. 2005,330:233-41.
[19]Genoux A, Dehondt H, Helleboid-Chapman A, et al. Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORalpha. Arterioscler Thromb Vasc Biol. 2005,25:1186-92.
[20]Hayhurst GP, Lee YH, Lambert G, et al. Hepatocyte nuclear factor 4-a (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol. 2001;21:1393-403.
[21]Tirona RG, Lee W, Leake BF, et al. The orphan nuclear receptor HNF4-a determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med. 2003;9:220-4.
[22]Prieur X, Schaap FG, Coste H, et al. Hepatocyte nuclear factor-4alpha regulates the human apolipoprotein AV gene: identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, AMP-activated protein kinase, and mi to gen-activated protein kinase pathway. Mol Endocrinol. 2005; 19:3107-25.
[23]Ito M, Takamatsu J, Matsuo T, et al. Serum concentrations of remnant-like particles in hypothyroid patients before and after thyroxine replacement. Clin Endocrinol (Oxf). 2003;58:621-6.
[24] Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev. 2001;81:1097-142.
[25]Prieur X, Huby T, Coste H, et al. Thyroid hormone regulates the hypotriglyceridemic gene APOAV. J Biol Chem. 2005;280:27533-43.
[26]Murao K, Wada Y, Nakamura T, et al. Effects of glucose and insulin on rat apolipoprotein A-I gene expression. J Biol Chem. 1998;273:18959-65.
[27] Chen M, Breslow JL, Li W, et al. Transcriptional regulation of the apoC-Ⅲ gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels. J Lipid Res. 1994;35:1918-24.
[28] Evert M, Schneider-Stock R, Dombrowski F. Apolipoprotein A-Ⅳ mRNA overexpression in early preneoplastic hepatic foci induced by low-number pancreatic islet transplants in streptozotocin-diabetic rats. Pathol Res Pract. 2003;199:373-9.
[29] Siri P, Candella N, Ko C, et al. Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B-lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance. J Biol Chem. 2001;276:46064-72.
[30] Yu Y-H, Ginsberg HN. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circ Res. 2005;96:1042-52.
[31]Miyashita Y, Shirai K, Itoh Y, et al. Low lipoprotein lipase mass in preheparin serum of type 2 diabetes mellitus patients and its recovery with insulin therapy. Diabetes Res Clin Pract. 2002;56:181-7.
[32]Nowak M, Helleboid-Chapman A, Jakel H, et al. Insulin-mediated down- regulation of apolipoprotein A5 gene expression through the phosphatidyhnositol 3-kinase pathway: role of upstream stimulatory factor. Mol Cell Biol. 2005;25:1537-48.
[33]Lefrancois-Martinez AM, Martinez A, et al. Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. J Biol Chem. 1995;270:2640-3.
[34]Nowak M, Helleboid-Chapman A, Jakel H, et al. Glucose regulates the expression of the apolipoprotein A5 gene. J Mol Biol. 2008;380:789-98.
[35]Lai CQ, Corella D, Demissie S, et al. Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study. Circulation. 2006; 113:2062-70.
[36]Tai ES, Corella D, Demissie S, et al. Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglycerides and apolipoprotein C3 concentrations in the Framingham Heart Study. J Nutr. 2005;135:397-403.