芝麻素对大鼠非酒精性脂肪性肝病的预防作用
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摘要
目的:用高脂膳食诱发大鼠脂肪肝模型,观察芝麻素对大鼠实验性非酒精性脂肪肝的预防作用并探讨其作用机制。
方法:健康雄性SD大鼠40只以普通饲料适应性喂养3天后,按体重及初始胆固醇水平随机分为5组,正常对照组、高脂模型组、芝麻素低、中、高剂量组(低、中、高剂量分别为20、40、80mg/kg·d~(-1))。9周后放血处死动物,测血清及肝匀浆中总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、、超氧化物岐化酶(SOD)、丙二醛(MDA);血丙氨酸氨基转移酶(ALT)门冬氨酸氨基转移酶(AST)及肝匀浆脂蛋白脂酶(LPL)、肝脂酶(HL)活力。逆转录PCR检测肝组织胆固醇7α羟化酶(CYP7A1)及肝细胞色素P450(CYP)2E1mRNA表达水平变化;肝组织切片观察肝脏病理改变。
结果:
1.高脂模型组肝指数明显高于正常对照组(P﹤0.05),芝麻素各剂量组肝指数较高脂模型组低(P﹤0.05),但三个剂量组之间无差异。
2.高脂模型组血清TC明显高于正常对照组(P﹤0.05),芝麻素中、高剂量组TC低于高脂模型组(P﹤0.01);各组大鼠TG无显著性差异(P﹥0.05);高脂模型组HDL-C低于正常对照组,芝麻素各剂量组HDL-C明显高于高脂模型组(P﹤0.01);高脂模型组LDL-C高于正常对照组(P﹤0.05),芝麻素各剂量组LDL-C低于高脂模型组(P﹤0.01)。
3.高脂模型组较正常对照组肝匀浆TC、TG、LDL-C均升高(P<0.05);芝麻素三个剂量组较高脂模型组TC、TG、LDL-C均下降(P<0.05)。随芝麻素剂量增加TC、TG、LDL-C含量逐渐下降(P<0.05)
4.高脂模型组LPL、ALT活性低于正常对照组,芝麻素高剂量组较高脂对照组LPL、ALT活性增高(P<0.05),其余各组间无统计学差异;各组间HL,AST无统计学差异。
5.高脂模型组血清及肝脏FFA含量高于正常对照组(P<0.05),芝麻素各剂量组FFA含量均低于高脂模型组(P<0.05),但各剂量组间无统计学差异。
6.高脂模型组、正常对照组及芝麻素各剂量组血清SOD无明显差异。高脂模型组较正常对照组肝匀浆SOD活力有所下降(P<0.01),芝麻素各剂量组SOD活力较高脂模型组均升高(P<0.01),且随芝麻素剂量增加SOD活力增加。高脂模型组血清及肝匀浆MDA含量较正常对照组高(P<0.01);芝麻素各剂量组MDA含量均低于高脂模型组(P<0.01),芝麻素各剂量组间差异无统计学意义。
7.与正常组相比,高脂模型组CYP7A1mRNA表达水平显著下降(P<0.05),芝麻素各组CYP7A1mRNA表达水平明显高于高脂模型组(P<0.05)。与正常组相比,高脂模型组CYP2E1mRNA表达水平显著增加(P<0.05),芝麻素各组CYP2E1mRNA表达水平明显低于高脂模型组(P<0.05)。
8.光镜观察下观察可见:正常对照组肝小叶结构完整、清晰,中央静脉大而壁薄,肝细胞排列成肝索,在中央静脉周围呈放射状排列;模型组大鼠肝组织见重度脂肪变,肝细胞体积增大,排列紊乱,索状结构不清,细胞内充满以大空泡为主的混合性空泡,部分伴肝细胞水样变,细胞核被挤向包膜,部分细胞核溶解,并伴炎细胞浸润;各芝麻素组脂肪变性肝细胞数量及程度明显较模型组轻,肝细胞肿胀不明显,细胞内脂滴较高脂组少,脂肪变以小泡性为主,细胞核居中,未见炎性细胞浸润。脂肪变细胞数量明显增多,无明显炎性细胞浸润。
结论:芝麻素能降低脂肪肝大鼠肝中脂质的含量,阻碍了初次打击对脂肪肝形成的作用;同时能显著增强SOD活性,减少氧化代谢产物MDA含量,显著降低CYP2E1mRNA的表达,因而能从提高机体抗氧化的能力,以及抑制CYP2E1mRNA表达方面阻断第二次打击对肝细胞脂肪病变的进展。因而对非酒精性脂肪肝有一定的预防作用。
Objective To study whether sesamin can prevent the development ofrats’nonalcoholic fatty liver disease.
Methods 40 SD rats were randomly divided into 5 groups according tothe initial serum cholesterol and weight．The normal control group，model group，and three doses of seamine groups（20、40、80mg/kg·d~(-1)）．After 9 weeks，TC，TG，LDL，HDL in liver and sera were determined by biochemistry analysis，andthe malondialdehyde(MDA) and superoxidedismutase(SOD) activity of hepatictissue and sera were measured．FFA, AST, ALT in sera and LPL,HL in liver werealso measured．The expression levels of cholesterol 7αhydroxylase (CYP7A1) andCytochrome P4502E1 mRNA in liver tissue were measured by reversetranscriptase-polymerase chain reaction (RT-PCR)．The liver pathology wasobserved under the light microscope．
Results
1. Liver/body weight index of model group was increased significantly comparedwith normal group(P﹤0.05).Compared with model group ,the treatment groupswere decreased markedly(P﹤0.05).
2. TC in sera of model group was increased significantly compared with normalgroup(P﹤0.05). Compared with model group, the middle and high dosestreatment groups were decreased markedly(P﹤0.05).TG had no significantdifferences. HDL in sera of model group was decreased significantly comparedwith normal group(P﹤0.05). Compared with model group, the treatmentgroups were increased markedly(P﹤0.05). LDL in sera of model group wasincreased significantly compared with normal group(P﹤0.05). Compared withmodel group, the treatment groups were decreased markedly(P﹤0.05)
3. TC,TG,LDL in liver of model group were increased significantly compared withnormal group(P﹤0.05,). Compared with model group, the treatment groupswere decreased markedly(P﹤0.05)
4. LPL and ALT in liver of model group were decreased significantly comparedwith normal group(P﹤0.05). Compared with model group, the high dosetreatment group were decreased markedly(P﹤0.05). HL and AST had nosignificant differences.
5. FFAs in both sera and liver of model groups were increased significantly compared with normal group(P﹤0.05). Compared with model group, thetreatment groups were decreased markedly(P﹤0.05)
6. SOD in sera had no significant differences. SOD in liver of model group wasdecreased significantly compared with normal group(P﹤0.01). Compared withmodel group, the treatment groups were increased markedly(P﹤0.01). MDA insera and liver of model group was increased significantly compared withnormal group(P﹤0.05). Compared with model group, the treatment groupswere decreased markedly(P﹤0.05).
7. The expression of CYP7A1 mRNA in model group was decreased significantlycompared with that of normal group(P<0.05).Compared with model group, thetreatment groups were increased remarkably(P﹤0.05).The expression ofCYP2E1 mRNA in model group was increased significantly compared with thatof normal group(P<0.05). Compared with model group, the treatment groupswere decreased remarkably(P﹤0.05).
8. Pathology observed by HE stain: Steatosis was not seen in controlled group,while severe lipid degeneration of liver were found in model group. Comparedwith model group, lipid degeneration in treatment groups were decreasedremarkably.
Conclusions Sesamin can decrease fat in liver, increase the activity ofSOD, and decrease MDA and the expression of CYP2E1. So, sesamin can preventthe development of rats＇nonalcoholic fatty liver disease.
方法:健康雄性SD大鼠40只以普通饲料适应性喂养3天后,按体重及初始胆固醇水平随机分为5组,正常对照组、高脂模型组、芝麻素低、中、高剂量组(低、中、高剂量分别为20、40、80mg/kg·d~(-1))。9周后放血处死动物,测血清及肝匀浆中总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、、超氧化物岐化酶(SOD)、丙二醛(MDA);血丙氨酸氨基转移酶(ALT)门冬氨酸氨基转移酶(AST)及肝匀浆脂蛋白脂酶(LPL)、肝脂酶(HL)活力。逆转录PCR检测肝组织胆固醇7α羟化酶(CYP7A1)及肝细胞色素P450(CYP)2E1mRNA表达水平变化;肝组织切片观察肝脏病理改变。
结果:
1.高脂模型组肝指数明显高于正常对照组(P﹤0.05),芝麻素各剂量组肝指数较高脂模型组低(P﹤0.05),但三个剂量组之间无差异。
2.高脂模型组血清TC明显高于正常对照组(P﹤0.05),芝麻素中、高剂量组TC低于高脂模型组(P﹤0.01);各组大鼠TG无显著性差异(P﹥0.05);高脂模型组HDL-C低于正常对照组,芝麻素各剂量组HDL-C明显高于高脂模型组(P﹤0.01);高脂模型组LDL-C高于正常对照组(P﹤0.05),芝麻素各剂量组LDL-C低于高脂模型组(P﹤0.01)。
3.高脂模型组较正常对照组肝匀浆TC、TG、LDL-C均升高(P<0.05);芝麻素三个剂量组较高脂模型组TC、TG、LDL-C均下降(P<0.05)。随芝麻素剂量增加TC、TG、LDL-C含量逐渐下降(P<0.05)
4.高脂模型组LPL、ALT活性低于正常对照组,芝麻素高剂量组较高脂对照组LPL、ALT活性增高(P<0.05),其余各组间无统计学差异;各组间HL,AST无统计学差异。
5.高脂模型组血清及肝脏FFA含量高于正常对照组(P<0.05),芝麻素各剂量组FFA含量均低于高脂模型组(P<0.05),但各剂量组间无统计学差异。
6.高脂模型组、正常对照组及芝麻素各剂量组血清SOD无明显差异。高脂模型组较正常对照组肝匀浆SOD活力有所下降(P<0.01),芝麻素各剂量组SOD活力较高脂模型组均升高(P<0.01),且随芝麻素剂量增加SOD活力增加。高脂模型组血清及肝匀浆MDA含量较正常对照组高(P<0.01);芝麻素各剂量组MDA含量均低于高脂模型组(P<0.01),芝麻素各剂量组间差异无统计学意义。
7.与正常组相比,高脂模型组CYP7A1mRNA表达水平显著下降(P<0.05),芝麻素各组CYP7A1mRNA表达水平明显高于高脂模型组(P<0.05)。与正常组相比,高脂模型组CYP2E1mRNA表达水平显著增加(P<0.05),芝麻素各组CYP2E1mRNA表达水平明显低于高脂模型组(P<0.05)。
8.光镜观察下观察可见:正常对照组肝小叶结构完整、清晰,中央静脉大而壁薄,肝细胞排列成肝索,在中央静脉周围呈放射状排列;模型组大鼠肝组织见重度脂肪变,肝细胞体积增大,排列紊乱,索状结构不清,细胞内充满以大空泡为主的混合性空泡,部分伴肝细胞水样变,细胞核被挤向包膜,部分细胞核溶解,并伴炎细胞浸润;各芝麻素组脂肪变性肝细胞数量及程度明显较模型组轻,肝细胞肿胀不明显,细胞内脂滴较高脂组少,脂肪变以小泡性为主,细胞核居中,未见炎性细胞浸润。脂肪变细胞数量明显增多,无明显炎性细胞浸润。
结论:芝麻素能降低脂肪肝大鼠肝中脂质的含量,阻碍了初次打击对脂肪肝形成的作用;同时能显著增强SOD活性,减少氧化代谢产物MDA含量,显著降低CYP2E1mRNA的表达,因而能从提高机体抗氧化的能力,以及抑制CYP2E1mRNA表达方面阻断第二次打击对肝细胞脂肪病变的进展。因而对非酒精性脂肪肝有一定的预防作用。
Objective To study whether sesamin can prevent the development ofrats’nonalcoholic fatty liver disease.
Methods 40 SD rats were randomly divided into 5 groups according tothe initial serum cholesterol and weight．The normal control group，model group，and three doses of seamine groups（20、40、80mg/kg·d~(-1)）．After 9 weeks，TC，TG，LDL，HDL in liver and sera were determined by biochemistry analysis，andthe malondialdehyde(MDA) and superoxidedismutase(SOD) activity of hepatictissue and sera were measured．FFA, AST, ALT in sera and LPL,HL in liver werealso measured．The expression levels of cholesterol 7αhydroxylase (CYP7A1) andCytochrome P4502E1 mRNA in liver tissue were measured by reversetranscriptase-polymerase chain reaction (RT-PCR)．The liver pathology wasobserved under the light microscope．
Results
1. Liver/body weight index of model group was increased significantly comparedwith normal group(P﹤0.05).Compared with model group ,the treatment groupswere decreased markedly(P﹤0.05).
2. TC in sera of model group was increased significantly compared with normalgroup(P﹤0.05). Compared with model group, the middle and high dosestreatment groups were decreased markedly(P﹤0.05).TG had no significantdifferences. HDL in sera of model group was decreased significantly comparedwith normal group(P﹤0.05). Compared with model group, the treatmentgroups were increased markedly(P﹤0.05). LDL in sera of model group wasincreased significantly compared with normal group(P﹤0.05). Compared withmodel group, the treatment groups were decreased markedly(P﹤0.05)
3. TC,TG,LDL in liver of model group were increased significantly compared withnormal group(P﹤0.05,). Compared with model group, the treatment groupswere decreased markedly(P﹤0.05)
4. LPL and ALT in liver of model group were decreased significantly comparedwith normal group(P﹤0.05). Compared with model group, the high dosetreatment group were decreased markedly(P﹤0.05). HL and AST had nosignificant differences.
5. FFAs in both sera and liver of model groups were increased significantly compared with normal group(P﹤0.05). Compared with model group, thetreatment groups were decreased markedly(P﹤0.05)
6. SOD in sera had no significant differences. SOD in liver of model group wasdecreased significantly compared with normal group(P﹤0.01). Compared withmodel group, the treatment groups were increased markedly(P﹤0.01). MDA insera and liver of model group was increased significantly compared withnormal group(P﹤0.05). Compared with model group, the treatment groupswere decreased markedly(P﹤0.05).
7. The expression of CYP7A1 mRNA in model group was decreased significantlycompared with that of normal group(P<0.05).Compared with model group, thetreatment groups were increased remarkably(P﹤0.05).The expression ofCYP2E1 mRNA in model group was increased significantly compared with thatof normal group(P<0.05). Compared with model group, the treatment groupswere decreased remarkably(P﹤0.05).
8. Pathology observed by HE stain: Steatosis was not seen in controlled group,while severe lipid degeneration of liver were found in model group. Comparedwith model group, lipid degeneration in treatment groups were decreasedremarkably.
Conclusions Sesamin can decrease fat in liver, increase the activity ofSOD, and decrease MDA and the expression of CYP2E1. So, sesamin can preventthe development of rats＇nonalcoholic fatty liver disease.
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[36]Videla LA, Rodrigo R,Araya J etal. Oxidative stress and depletion of hepatic long-chainpolyunsaturated fatty acids may contribute to nona1coho1ic fatty liver disease. Free Radic BiolMed.2004;37(9):1499-507.
[37]Perez CarrerasM，DelHoyoP，MartinMA，etal. Defective hepatic mitochondrial respiratorychain in patients with nonaleoholic steatohepatitis.Hepatology.2003;38(4):999-1007.
[38] KorukM，Taysi S，SavasMC，etal.Oxidative stress and enzymatic antioxidant status inpatients with nonalcoholic steatohepatitis. Ann C1in Lab Sci.2004;34(1):57-62.
[1]周建新，孙明，汪海峰等.芝麻素的应用性能研究.食品科学，2004，25（1）：102-105.
[2]戴洪平，王兴国，余春涛.芝麻素的研究及开发.中国油脂,2003,28(6):52-54.
[3] Ikeda,T .Nishijima,Y. etal .Protective effect of sesamin administration on exercise-inducedlipid peroxidation[J] . International Journal of Sports Medicine，2003,24(7 ): 53 0 -5 34.
[4]Ogawa,Hiroshi et al .Sesame lignans modulate cholesterol metabolism in the stroke-pornespontaneously hypertensive rat[ J ]，.Clinical and Experimental Pharmacology and Physiology,1995，22(SUPPL.1 ):S310-S312
[5] Ide, Takashi: Sesamin, a sesame lignan, as a potent serumlipid -lowering food component.JARQ[ J]，2003,37(3 ): 151 -158
[6]Matsumura, Yasuo et al. Effects of sesamin on altered vascular reactivity in aortic rings ofdeoxycorticosterone acetate- salt -induced hypertensive rat[J〕.Chemical and PharmaceuticalBulletin(Tokyo)2000，48(9):1041 - 1045.
[7]Nakano, Daisuke et al. Efects of sesamin on aortic oxidative stress and endothelialdysfunction in deoxycorticosterone acetate-salt hypertensive rats[J].Biological&PharmaceuticalBulletin,2003,26(12):1701-1705
[8]Lee CC，Chen PR，Tsai SC．Sesaminin duces nitricoxid and decrease endothelin-1 productionin HUVEs：possible implication for its antihypertensive effect．J．Hyperterteus，2004，Dec．22 (12):2329-2338
[9]黄凯,杨解人,周勇. L 2芝麻素对代谢综合征大鼠心肌损伤的抑制作用.中国药理学与毒理学杂志,2008,22(5):341-347.
[10]关立克，王淑兰.芝麻素对动脉硬化斑块形成及主动脉壁血管细胞黏附分子- 1表达的影响.现代预防医学,2009,36(15):2958-2960
[11]周勇,杨解人.芝麻素对高脂、高糖饲养大鼠血脂血糖及血管重构的影响.中国病理生理杂志, 2008, 24 (7) : 1286– 1291
[12]安建博，张瑞娟，周玲.芝麻素对高脂血症大鼠糖代谢的作用.营养学报, 2010,32(2):145-148
[13]Miyahara, Yoshiyuki et al. Sesamin and episesamin induce apoptosi in human lymphoidleukemia Molt 4B cells[J] .International Journal of Molecular Medicine,2000,6(1):43-46.
[14]Hibasami,Hiroshige et al ;Induction of apoptosis by Acanthopanax senticosus HARMS andits component,sesamin in human stomach cancer KATOIII cells[J] .Oncology Reports, 2007( 6):1213-1216.
[15] Dachtler, Markusetal. Online LC-NMR-MS characterization of sesame oil extracts andassessment of their antioxidant activity[J].European Journal of Lipid Science and Technology,2003,105( 9):488-496
[1]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组．非酒精性脂肪性肝病诊疗指南[J]．实用肝脏病杂志，2007，10（1）：11．
[2]Bedogni G Bellentani S．Fatty liver how frequent is it and why [J]．Ann Hepatology，2004，3：63.
[3]Neuschwander-Tetri BA，Caldwell SH．Nonalcoholic steatohepatitis summary of an AASLDSingle Topic Conference[J]．Hepatology，2003，38：536．
[4]Angulo P，Keach J，Batts K，et a1.Independent predictors of liver fibrosis in patients withnonalcoholic steatohepatitis Hepatology，1999，30：1356-1362.
[5]Caldwell S，Oelsner D，Iezzoni J，et al.Cryptogenic cirrhosis：clinical characterization andrisk factors for undering disease Hepatology，1999，29：664-669．
[6] Day CP. The potential roal of genes in nonalcoholic fatty liver disease[ J ]. Clin LiverDis,2004, 8 (3) : 673-691
[7]范建高．代谢综合征与脂肪肝[J]．国外医学·内分泌学分册，2002，22（9）：273-275.
[8]严克贵，郑吉平，等．行为生活方式等因素与脂肪肝患病关联性研究[J]．现代预防医学，2009，36（1）：19-22.
[9]Day C，James O Steatohepatitis: A tale of two“hits”?Gastroenterology，l998，114：842-845．
[10]Yoon D，Lee SH，Park HS，et al.Hypoadipo -ncctincmia and ins ulin resistance arcassociatedwith nonalcoholic fatty liver disease J Korean Med Sci，2005，20（3）：421-426．
[11]Hanley A.I Williams K，Festa A，et al. Liver markers and development of the metabolicsyndrome the insulin resistance atherosclerosis study [J]．Diabetes，2005，54（11）：3140
[12]Li ZP , Yang SQ , Lin HZ,et al1 Probiotics and antibodies to TNF in hibit inflammatoryactivity and improvr nonalcoholic fatty liver disease[J ].Hepatology , 2003 , 37(2) :343-350.
[13]Saksena S，Daly AK，Leathart JB，et al.Manganese dependent superoxide dismutase(SOD2)targeting sequence polymorphism is associated with advanced fibrosis in patients withnonalcoholic fatty liver disease[J].J Hepatol，2003；38(Suppl2)：47
[14]Zhang X, Qi R ,Xian X, et al1Spontaneous atherosclerosis in aged LPL deficient mice withsevere hypertriglyceridemia on a normal chow diet [J ]. Circ1 Res, 2008 :102 :250-256
[15]Wang J Y,Xian XD ,Huang W. et al1 Expression of LPL in endothelial intact artery results inlipid deposition and vascular cell adhesion molecule-1upregulation in both LPL andapoE-deficient mice [ J ].Arterioscler Thromb Vasc Biol ,2007 ,27 :197-203.
[16] Eberle D, Clement K,Meyre D, et al. SREBF21 gene polymorphism are associated withobesity and type 2 diabetes in French obese and diabetic cohorts[ J ]. Diabetes, 2004, 53 (8) :2153-2157.
[17]谢翔,马依形,王迎洪,等.汉族人群SREBP2lc的基因54G/C多态性与急性心肌梗死相关性研究[ J ] .现代生物医学进展,2008, 8 (3) : 488-490.
[18]胡中扬,张乐,杨期东,等. ApoB基因多态性与长沙汉族人群脑出血的关系及其对血脂水平的影响[ J ].中南大学学报, 2008, 33(6) : 494-498.
[19]Bouchard L,Weisnagel SJ, Engert JC, et al. Human resistin gene polymorphism is associatedwith visceral obesity and fasting and oral glucose stimulated C2pep tide in the Québec FamilyStudy[ J ]. J Endcrinol Invest, 2004, 27 (11) : 1003-1009.
[20]赖晓波,聂玉强,李瑜元,等.瘦素基因多态性与非酒精性脂肪性肝病及胰岛素抵抗的相关性[ J ].中华消化杂志, 2008, 28(2) : 126-127.
[21]杨辉,李瑜元,聂玉强,等.过氧化物酶体增殖因子活化受体2γ基因多态性与非酒精性脂肪性肝病及脂联素的关系[ J ].中华消化杂志, 2008, 28 (2) : 113-115.
[22]Younossi ZM, Gorreta F,Ong JG, etal. Hepatic gene exp ression in patientswithobesity2related non2alcoholic steatohepatitis[ J ]. Liver International, 2005, 25 (4) : 760-771.
[23]张桂灵,石小枫,刘杞.非酒精性脂肪肝的药物治疗现状[J ] .现代医药卫生,2004 ,20(23) :25192-521.
[24]李俊峰,杨冬华.非酒精性脂肪性肝病的药物治疗[J ] .临床荟萃,2004 ,19(22) :1304-1306.
[25]于艳秋.前列腺素E1治疗老年脂肪肝疗效观察[J ] .实用老年病学,2000 ,14 (2) :92293.
[2]Day CP, James OF. Steatohepatitis:a tale of two“hits”?[J].Gastroenterology,1998;114(4):842-845.
[3]范建高，曾民德.脂肪性肝病[M].第一版，北京:人民卫生出版社，2005，237-238
[4]Angulo P, KeachJC,BattKP，et al.Independent predictors of liver cirrhosis in Patient withnonaleoholic steatohePatitis. HePatolog，1999;(30):1356-1362.
[5]Sanyal AJ,Campbell-Sargent C,Mirshahi F,et a1.Nonalcoholic steatohepatitis：association ofinsulin resistance and mitochondrial abnormalities[J]．Gastroenterology，2001;120(5)：l183-l192．
[6]李清漪,毛一卿,张金树,等.泰脂安对高脂饮食家兔血脂的影响〔J〕.中国临床药理学与治疗学, 2006; 11 (9) : 991-993
[7]阎明，吕瑞娟.两种调脂药对高脂血症性脂肪肝治疗的实验性研究.中华肝脏病杂志，2001;9（6）：355-357
[8]孙大炜，孙宝华，徐晓莉，等.他汀类调脂药治疗脂肪肝的试验性研究[J].哈尔滨医药，2006;26(5):60-61
[9]邓建伟，郭栋，周宏濒.他汀类降血脂药物的药代动力学研究进展[J].中国临床药理学与治疗学，2007;12(8):850-860
[10]Nakai T，Harada Y，Novel antioxidative metabolites in rat liver eated sesamin Joumal ofAgricultural and Food Chemist,2003;51(6):1666-1670
[11]Kahashi M，Fukuda H.sesamin(asesamelignan)deereases fatty acid synthesisin rat Liveraceom Panying the down-regulation of sterol regulatory element binding Protein-1. BiochimieaetBioPhysiea-Acta(Japan)，2001;1534(l)l-13
[12] Ikeda T，Nishijima Y etal .Protective effect of sesamin administration on exercise-inducedlipid peroxidation[J] . International Journal of Sports Medicine，2003;24(7 ): 530 -534.
[13]Ogawa H, Hiroshi F etal .Sesame lignans modulate cholesterol metabolism in thestroke-porne spontaneously hypertensive rat[ J ] .Clinical and Experimental Pharmacology andPhysiology, 1995;22(1 ):310-312
[14]汪五三,宋建国.芝麻素保肝作用实验研究.中药药理与临床[J],2006; 22 (3、4):27-31
[15]黎满全，白静，贾莱梅，吴佩柱.广州地区部分健康人群催患高脂血症、高血糖、脂肪肝的现状调查[J].中国国境卫生检疫杂志，2005;28(3):141-143
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[19]Goehee PA，Jonsson JR，Clouston AD，etal. Steatosis in chronic hepatitis C: association withincreased messenger RNA expression of collagen l，tumor necrosis faetor-alpha andcytoehromeP4502E1.JGastroenterol HePatol. 2003;18(4):386-392.
[20]Emery MG，Fisher JM，Chien JY，etal.CYP2E1 activity before and after weight loss inmorbidly obese subjcetswith nonaleoholic fatty liverdisease.Hepatology.2003;38(2):428-435.
[21]张静喆,梁晓强.清胆胶囊对胆固醇结石小鼠肝脏中PPAR-γ、CYP7A1及NF-κB表达的影响[J].中国中西医结合消化杂志,2010;18(4):254-259.
[22]Gupta S, Pandak WM, Hylemon PB.LXR alpha is the dominant regulator of CYPTAItranscription[J].Biochem Biophys Res Common,2002;(293):338-343.
[23]Van EckM, Zim mermann R, Groot PH, et a.l ArteriosclerThromb Vasc Biol ,2000; 20(9)∶53-62
[24] Pulinilkunnil T，Rodrigues B．Cardiac lipoprotein lipase：meta-bolic basis for diabetic heartdisease[J]．Cardiovasc Res，2006;69(2)：329-340．
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[26]VeceraR, SkottovaN, Vana P, eta.l Antioxidant status, lipo protein pro-file and liver lipids inrats fed on high-cholesterold ietco ntainingc urranto ilri chin n-3 and n-6 polyunsaturatedf attyacids. PhysiolR es, 2003; 5 2(2)∶177-187
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[29]夏瑾瑜，贾学平，程良斌等.肝脂康胶囊对非酒精性脂肪肝的防治作用[J].中国中西医结合消化杂志，2004，12(l:)15-18.
[30]Younossi ZM, Diehl AM, Ong JP. Nonalcoholic Fatty Liver Disease: An agenda for clinicalresearch[J].Hepatology,2002;35:746-752.
[31]戴宁，曾民德，李继强等.复方中药抑制非酒精性脂肪肝肝细胞色素P4502E1表达的实验研究[J].中国中西医结合杂志，2000，20(6):453-456.
[32]WuD，CederbaumAl·Cyelosporine A protects against arachidonic acid toxieity in rathepatoeytes:role ofCYP2El and mitoehondria[J].HePatolog，y2002，35:1420-1430.
[33]DemeilliersC，MaisonneuveC，GrodetA，etal.Impaired adaptive resunthesis and prolongeddepletion of hepatic mitoehondrial DNA after repeated alcohol binges in mice[J].Gastroenterolog，2002;123:1278-1290.
[34]RouaehH，Fataceioli，VGentilM，etal.Eeffct of chronic ethanol feeding on lipid peroxdationand protein oxidation inrelation to liver Pathology[J].HePatolog，1997;25:351-355.
[35]NietoN，FriedmanSL，Greenwel，Petal.CYP2E1-mediated oxidative stress induces collagentype1 expression in rat hepatie stellate cells. [J].HePatolog，1999;30:987-996.
[36]Videla LA, Rodrigo R,Araya J etal. Oxidative stress and depletion of hepatic long-chainpolyunsaturated fatty acids may contribute to nona1coho1ic fatty liver disease. Free Radic BiolMed.2004;37(9):1499-507.
[37]Perez CarrerasM，DelHoyoP，MartinMA，etal. Defective hepatic mitochondrial respiratorychain in patients with nonaleoholic steatohepatitis.Hepatology.2003;38(4):999-1007.
[38] KorukM，Taysi S，SavasMC，etal.Oxidative stress and enzymatic antioxidant status inpatients with nonalcoholic steatohepatitis. Ann C1in Lab Sci.2004;34(1):57-62.
[1]周建新，孙明，汪海峰等.芝麻素的应用性能研究.食品科学，2004，25（1）：102-105.
[2]戴洪平，王兴国，余春涛.芝麻素的研究及开发.中国油脂,2003,28(6):52-54.
[3] Ikeda,T .Nishijima,Y. etal .Protective effect of sesamin administration on exercise-inducedlipid peroxidation[J] . International Journal of Sports Medicine，2003,24(7 ): 53 0 -5 34.
[4]Ogawa,Hiroshi et al .Sesame lignans modulate cholesterol metabolism in the stroke-pornespontaneously hypertensive rat[ J ]，.Clinical and Experimental Pharmacology and Physiology,1995，22(SUPPL.1 ):S310-S312
[5] Ide, Takashi: Sesamin, a sesame lignan, as a potent serumlipid -lowering food component.JARQ[ J]，2003,37(3 ): 151 -158
[6]Matsumura, Yasuo et al. Effects of sesamin on altered vascular reactivity in aortic rings ofdeoxycorticosterone acetate- salt -induced hypertensive rat[J〕.Chemical and PharmaceuticalBulletin(Tokyo)2000，48(9):1041 - 1045.
[7]Nakano, Daisuke et al. Efects of sesamin on aortic oxidative stress and endothelialdysfunction in deoxycorticosterone acetate-salt hypertensive rats[J].Biological&PharmaceuticalBulletin,2003,26(12):1701-1705
[8]Lee CC，Chen PR，Tsai SC．Sesaminin duces nitricoxid and decrease endothelin-1 productionin HUVEs：possible implication for its antihypertensive effect．J．Hyperterteus，2004，Dec．22 (12):2329-2338
[9]黄凯,杨解人,周勇. L 2芝麻素对代谢综合征大鼠心肌损伤的抑制作用.中国药理学与毒理学杂志,2008,22(5):341-347.
[10]关立克，王淑兰.芝麻素对动脉硬化斑块形成及主动脉壁血管细胞黏附分子- 1表达的影响.现代预防医学,2009,36(15):2958-2960
[11]周勇,杨解人.芝麻素对高脂、高糖饲养大鼠血脂血糖及血管重构的影响.中国病理生理杂志, 2008, 24 (7) : 1286– 1291
[12]安建博，张瑞娟，周玲.芝麻素对高脂血症大鼠糖代谢的作用.营养学报, 2010,32(2):145-148
[13]Miyahara, Yoshiyuki et al. Sesamin and episesamin induce apoptosi in human lymphoidleukemia Molt 4B cells[J] .International Journal of Molecular Medicine,2000,6(1):43-46.
[14]Hibasami,Hiroshige et al ;Induction of apoptosis by Acanthopanax senticosus HARMS andits component,sesamin in human stomach cancer KATOIII cells[J] .Oncology Reports, 2007( 6):1213-1216.
[15] Dachtler, Markusetal. Online LC-NMR-MS characterization of sesame oil extracts andassessment of their antioxidant activity[J].European Journal of Lipid Science and Technology,2003,105( 9):488-496
[1]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组．非酒精性脂肪性肝病诊疗指南[J]．实用肝脏病杂志，2007，10（1）：11．
[2]Bedogni G Bellentani S．Fatty liver how frequent is it and why [J]．Ann Hepatology，2004，3：63.
[3]Neuschwander-Tetri BA，Caldwell SH．Nonalcoholic steatohepatitis summary of an AASLDSingle Topic Conference[J]．Hepatology，2003，38：536．
[4]Angulo P，Keach J，Batts K，et a1.Independent predictors of liver fibrosis in patients withnonalcoholic steatohepatitis Hepatology，1999，30：1356-1362.
[5]Caldwell S，Oelsner D，Iezzoni J，et al.Cryptogenic cirrhosis：clinical characterization andrisk factors for undering disease Hepatology，1999，29：664-669．
[6] Day CP. The potential roal of genes in nonalcoholic fatty liver disease[ J ]. Clin LiverDis,2004, 8 (3) : 673-691
[7]范建高．代谢综合征与脂肪肝[J]．国外医学·内分泌学分册，2002，22（9）：273-275.
[8]严克贵，郑吉平，等．行为生活方式等因素与脂肪肝患病关联性研究[J]．现代预防医学，2009，36（1）：19-22.
[9]Day C，James O Steatohepatitis: A tale of two“hits”?Gastroenterology，l998，114：842-845．
[10]Yoon D，Lee SH，Park HS，et al.Hypoadipo -ncctincmia and ins ulin resistance arcassociatedwith nonalcoholic fatty liver disease J Korean Med Sci，2005，20（3）：421-426．
[11]Hanley A.I Williams K，Festa A，et al. Liver markers and development of the metabolicsyndrome the insulin resistance atherosclerosis study [J]．Diabetes，2005，54（11）：3140
[12]Li ZP , Yang SQ , Lin HZ,et al1 Probiotics and antibodies to TNF in hibit inflammatoryactivity and improvr nonalcoholic fatty liver disease[J ].Hepatology , 2003 , 37(2) :343-350.
[13]Saksena S，Daly AK，Leathart JB，et al.Manganese dependent superoxide dismutase(SOD2)targeting sequence polymorphism is associated with advanced fibrosis in patients withnonalcoholic fatty liver disease[J].J Hepatol，2003；38(Suppl2)：47
[14]Zhang X, Qi R ,Xian X, et al1Spontaneous atherosclerosis in aged LPL deficient mice withsevere hypertriglyceridemia on a normal chow diet [J ]. Circ1 Res, 2008 :102 :250-256
[15]Wang J Y,Xian XD ,Huang W. et al1 Expression of LPL in endothelial intact artery results inlipid deposition and vascular cell adhesion molecule-1upregulation in both LPL andapoE-deficient mice [ J ].Arterioscler Thromb Vasc Biol ,2007 ,27 :197-203.
[16] Eberle D, Clement K,Meyre D, et al. SREBF21 gene polymorphism are associated withobesity and type 2 diabetes in French obese and diabetic cohorts[ J ]. Diabetes, 2004, 53 (8) :2153-2157.
[17]谢翔,马依形,王迎洪,等.汉族人群SREBP2lc的基因54G/C多态性与急性心肌梗死相关性研究[ J ] .现代生物医学进展,2008, 8 (3) : 488-490.
[18]胡中扬,张乐,杨期东,等. ApoB基因多态性与长沙汉族人群脑出血的关系及其对血脂水平的影响[ J ].中南大学学报, 2008, 33(6) : 494-498.
[19]Bouchard L,Weisnagel SJ, Engert JC, et al. Human resistin gene polymorphism is associatedwith visceral obesity and fasting and oral glucose stimulated C2pep tide in the Québec FamilyStudy[ J ]. J Endcrinol Invest, 2004, 27 (11) : 1003-1009.
[20]赖晓波,聂玉强,李瑜元,等.瘦素基因多态性与非酒精性脂肪性肝病及胰岛素抵抗的相关性[ J ].中华消化杂志, 2008, 28(2) : 126-127.
[21]杨辉,李瑜元,聂玉强,等.过氧化物酶体增殖因子活化受体2γ基因多态性与非酒精性脂肪性肝病及脂联素的关系[ J ].中华消化杂志, 2008, 28 (2) : 113-115.
[22]Younossi ZM, Gorreta F,Ong JG, etal. Hepatic gene exp ression in patientswithobesity2related non2alcoholic steatohepatitis[ J ]. Liver International, 2005, 25 (4) : 760-771.
[23]张桂灵,石小枫,刘杞.非酒精性脂肪肝的药物治疗现状[J ] .现代医药卫生,2004 ,20(23) :25192-521.
[24]李俊峰,杨冬华.非酒精性脂肪性肝病的药物治疗[J ] .临床荟萃,2004 ,19(22) :1304-1306.
[25]于艳秋.前列腺素E1治疗老年脂肪肝疗效观察[J ] .实用老年病学,2000 ,14 (2) :92293.