摘要
一、研究背景
近10年来,在我国脂肪肝尤其是非酒精性脂肪肝(NAFLD)的患病率明显上升,2004年上海成人脂肪肝的患病率为20.82%,与国外脂肪肝的患病率相接近。在西方国家,脂肪肝已经成为最常见的肝病;在国内,脂肪肝也有取代病毒性肝炎成为最常见肝病的趋势。然而肝脂肪变性的临床意义一直存在争论。长期以来,人们认为脂肪肝是一种预后良好的疾病,特别是当这些脂肪肝患者血清转氨酶正常时。但近年来,越来越多的研究发现脂肪肝与许多威胁生命的疾病密切相关。
非酒精性脂肪肝与肥胖密切相关。研究发现,肝脏脂肪代谢与许多调节能量代谢维持组织完整性的代谢产物、激素、细胞因子和神经介质的作用相关,如肿瘤坏死因子-α、瘦素、脂联素等。脂肪肝不仅仅是代谢障碍的不良结果,它也能触发信号使得肝内脂肪代谢正常化,这样就不可避免地也改变了在其他组织中调节脂肪代谢的细胞因子、激素和神经介质的活性。这些因素相互作用,将引起神经体液和免疫系统的功能障碍,导致胰岛素抵抗、代谢综合征等的发生。
β(1→3)(1→4)D-葡聚糖(简称β-葡聚糖)是从燕麦或大麦中提取的多聚糖。其基本结构是由D葡萄糖以β(1→3)(1→4)糖苷键连接而成的线性多糖,属于可溶性食物纤维。已有实验研究证实燕麦β-葡聚糖具有抗氧化、降血脂、降血糖、保护肝脏功能、促进肠内益生菌生长等作用,但这些研究既局限于单病种的实验动物模型,也局限于治疗改善,对其作用机制研究较少。
本课题基于现今关于NAFLD和肥胖的最新研究进展,用高脂、高能饲料制备符合临床特点的肥胖与肥胖抵抗型NAFL大鼠模型,研究肥胖与NAFL的关系,肥胖在NAFLD发生、发展的中的作用,采用目前最先进的实时荧光定量PCR技术,研究肥胖与肥胖抵抗型NAFL大鼠内脏脂肪PPAR-γmRNA、UCP2mRNA的表达调控作用;并进行为期4w的β-葡聚糖干预实验研究,观察燕麦β-葡聚糖及饮食调整对改善NAFL大鼠肥胖、血脂紊乱、高血糖、胰岛素抵抗等作用,为进一步探讨NAFLD的防治机制及功能性保健食品的开发提供实验依据。
二、研究内容
第一部分
目的:用高脂、高能饲料制备肥胖与肥胖型非酒精性脂肪肝大鼠模型。
方法:清洁级雄性健康Sprague-Dawley(SD)大鼠140只,体重(100g±10g),按体重随机抽取20只,作为空白对照组,剩余120只用于制备肥胖与肥胖抵抗型大鼠NAFL模型。肥胖型NAFL组(O-N):每鼠每天自由饮水及进食造模饲料,连续造模8w后即至造模成功时,体重大于C组的平均体重+1.96倍标准差的,分为O-N组;肥胖抵抗型NAFL组(OR-N):每鼠每天自由饮水及进食造模饲料,连续造模8w后即至造模成功时,体重小于C组的平均体重+1.0倍标准差的,分为OR-N组。
大鼠自由进食,每天观察大鼠的一般状况、饮食变化、行为(自主活动、精神状态)变化、毛发变化,每天称量饲料,每周称量大鼠体重,造模0、4w、8w时监测血糖、血脂情况,8w结束造模实验,每组随机取8只处死,采集标本检测:肝指数,血清ALT、AST、TC、TG,肝脏病理。
结果:O-N与OR-N组大鼠在喂养期间体重差距逐渐增大,至第8周喂养结束时,O-N组体重显著高于OR-N组及正常对照组;两组ALT、TG均显著升高,而O-N组大鼠血清TC、TG显著高于OR-N组;两组肝重量及肝指数均显著升高,O-N组肝重量及体重均显著高于OR-N组,但肝指数间未见显著差异;O-N组、OR-N组肝小叶结构破坏,肝索排列紊乱,肝窦扩张,肝细胞肿胀明显,细胞质内可见大小不等,数量不一的圆形脂肪空泡。
第二部分
目的:研究肥胖与肥胖抵抗型非酒精性脂肪肝大鼠间代谢差异及产生机制。
方法:清洁级雄性健康Sprague-Dawley(SD)大鼠24只,分别来源于造模8W后,所形成的肥胖型非酒精性脂肪肝大鼠、肥胖抵抗型非酒精性脂肪肝大鼠和正常对照组,每组随机抽取8只,肥胖倾向的为O-N组、肥胖抵抗的为OR-N组和正常对照组。
在第8 W时,大鼠禁食12h后,用10%水合氯醛麻醉,眼眶及腹主动脉取血,测定TC、TG、HDL、LDL、leptin、Il-6、TNF-α,测血糖及计算胰岛素敏感指数;血取净后,立即进行解剖,观察主要脏器,剥离肾周及睾周脂肪组织垫,用滤纸吸干组织液后称重,计算脂体比;留取左侧肾周脂肪组织,部分左叶肝脏,于10%福尔马林溶液中固定,用于脂肪组织病理检测;同时迅速分离下丘脑置液氮中保存,用于NPY含量测定。
结果:至造模结束时,O-N组大鼠能量摄入及利用率明显高于OR-N组和空白对照组;O-N组大鼠肾周脂肪垫、睾周脂肪垫重量、FINS、ISI、Leptin血清含量、血清NPY含量、下丘脑NPY含量显著高于正常对照组和OR-N组,但两组间脂体比、TNF-α、IL-6血清含量、FBG、LDL未见显著差异;在400倍显微镜视野下,O-N组和OR-N组大鼠左侧肾周脂肪细胞直径显著增加,体积变大。
第三部分
目的:研究UCP2和PPARγ2在肥胖与肥胖抵抗型非酒精性脂肪肝大鼠形成中的作用。
方法:两步法实时荧光定量逆转录聚合酶链反应检测脂肪组织和肝脏组织PPARγ2、UCP2 mRNA表达。
结果:OR-N组肝脏及脂肪组织中UCP2 mRNA相对表达量均显著高于O-N组和正常对照组,脂肪组织中PPARγ2 mRNA相对表达量显著低于正常对照组;O-N组肝脏中UCP2 mRNA相对表达量显著低于正常对照组,脂肪组织中PPARγ2 mRNA相对表达量均显著高于OR-N组和正常对照组。
第四部分
目的:研究β-葡聚糖和恢复正常饮食对肥胖与非酒精性脂肪肝的作用。
方法:清洁级雄性健康Sprague-Dawley(SD)大鼠56只,分别来源于造模8周后,所形成的肥胖型非酒精性脂肪肝大鼠、肥胖抵抗型非酒精性脂肪肝大鼠和正常对照组,将肥胖与肥胖抵抗型NAFL大鼠分别随机分为3组,每组8只,分别为O-N-1组、O-N-2组、O-N-3组和OR-N-1组、OR-N-2组、OR-N-3组;正常大鼠8只为对照组。空白对照组进食普通饲料;O-N-1组、OR-N-1组给予500mg/kg.dP-1β-葡聚糖灌胃干预;O-N-2组、OR-N-2组持续高脂饮食;O-N-3组、OR-N-3组恢复正常饮食。
在干预第4W结束时,大鼠禁食12h后,用10%水合氯醛麻醉,眼眶及腹主动脉取血,测定TC、TG、HDL、LDL、ALT、AST。血取净后,立即进行解剖,观察主要脏器,剥离肾周及睾周脂肪组织垫,用滤纸吸干组织液后称重,计算脂体比、肝体比;留取部分左叶肝脏,于10%福尔马林溶液中固定用于病理观察;留取部分左叶肝脏,于液氮中保存,用于SOD、MDA含量测定。
结果:O-N各组体重仍显著高于正常对照组,OR-N-1组与OR-N-2组体重也显著升高,其中OR-N-2组体重增长显著高于正常组体重增长。O-N-2组与OR-N-2组大鼠脂体比显著增高,O-N-1组与OR-N-1组虽然仍高于正常对照组,但与同组的2组相比,均有下降趋势,O-N-1组与O-N-3组大鼠相较O-N-2组,脂体比显著降低,OR-N-3组大鼠相较OR-N-2组,脂体比显著降低。O-N-2组的TC、TG、LDL显著升高,而HDL显著降低,OR-N-2组TG、LDL显著升高;与O-N-2组相比,O-N-1组TC显著降低,O-N-3组TG显著降低,HDL显著升高;与OR-N-2组相比,OR-N-1组TG显著降低。O-N-2组ALT、肝指数显著高于正常对照组和O-N-3组;OR-N-2组ALT显著高于正常对照组和OR-N-3组,肝指数显著高于正常对照组;各组AST未见显著差异。O-N-1组与OR-N-1组SOD活性显著高于正常对照组,O-N-2组与OR-N-2组SOD活性显著低于正常对照组;MDA含量O-N-1组和O-N-3组显著低于O-N-2组,OR-N-1组显著低于OR-N-2组,O-N-2组和OR-N-2组显著高于正常对照组。
三、结论
1.用高脂高能饲料成功制备肥胖与肥胖抵抗型非酒精性脂肪肝大鼠模型。
2.肥胖与肥胖抵抗型非酒精性脂肪肝大鼠中,均发现体脂比升高、血脂代谢紊乱、血糖、TNF-α、IL-6升高及胰岛素抵抗现象,血脂代谢紊乱是非酒精性脂肪肝发生的始动原因。
3.肥胖抵抗的发生可能是由于内脏脂肪组织UCP2 mRNA的表达水平升高,PPARγ2 mRNA的表达受到抑制,减少脂肪细胞分化,减轻瘦素抵抗及胰岛素抵抗,降低NPY含量,从而减少能量摄入及利用率,增加能量消耗,避免肥胖的发生。
4.肝脏组织中UCP2 mRNA的表达水平显著升高,可能超过机体代偿能力而产生不利影响,对肝脏造成损伤。
5.恢复正常饮食和β-葡聚糖能够抑制肥胖倾向大鼠体重增长,降低血清胆固醇及体脂肪含量,改善非酒精性脂肪肝。
6.肥胖抵抗型大鼠在高脂、高能饮食诱导下,体重增长开始快于肥胖倾向大鼠,提示长期高脂饮食可能会导致肥胖抵抗大鼠继而出现肥胖。
Background
In the past 10 years, the prevalence rate of fatty liver disease, especially non-alcoholic fatty liver disease (NAFLD) had obviously increased. In Shanghai China, the prevalence rate is 20.82% close to foreign countries. In western countries, fatty liver has become the most common liver disease. In China, fatty liver also has replaced viral hepatitis as the most common liver disease trends. However, the clinical significance of hepatic steatosis is controversial. A long time, people think fatty liver is a kind of disease with good prognosis, especially when these fatty liver patients with normal serum aminotransferase. But in recent years, more and more studies have found fatty liver are closely related with many life-threatening diseases.
Non-alcoholic fatty liver and obesity are closely related. The study found that liver fat metabolism has related with the metabolites, hormones, cytokines and nerve media such as tumor necrosis factor-α, leptin, adiponectin and so on. Metabolism of fatty liver is not only the undesirable result of dysbolism, it can also trigger signal makes the normalization of liver fat metabolism. But it inevitably also changed the activity of cytokines, hormones and neural in the other organizations. These factors interact to cause neurohumoral and immune system dysfunction, leading to insulin resistance and metabolic syndrome happen.
D-glucan(1→3) (1→4) is a kind of polysaccharide extracted from oats or barley and belongs to soluble dietary fiber. Experimental study has confirmed that oatβ-glucan has the functions such as anti-oxidation, reducing blood fat, lowering blood sugar, protecting liver function, and promote the growth of intestinal probiotics, etc. But these studies only confined to single disease in experimental animal models or treatment. The study about mechanism is still less.
This study is based on the latest research progress of NAFLD and obesity, with high-fat and high-energy feed prepared animal model which has the clinical features of NAFLD with obesity and obesity-resistant. It aimed to find out the relationship between obesity and NAFLD, and the role of obesity in the occurrence and development of NAFLD. Using real-time fluorescence quantitative PCR technique studies the expression and regulation of PPAR-γand UCP2 in obesity and obesity-resistant NAFLD rats. And takingβ-glucan and diet intervention study for 4weeks observed the function, in order to further explore the mechanism and prevention of NAFLD and provide experimental basis for health food products.
PartⅠPrepare obesity and obesity-resistant model in nonalcoholic fatty liver rats
Objective To use high-fat and high-energy feedstuff prepare obesity and obesity-resistant model in nonalcoholic fatty liver rats.
Method 20 male Sprague-Dawley (SD) rats were randomly selected according to the weight as control group, the remaining 120 for the model group. After 8 weeks, the average weight of +1.96 times the standard deviation divided into O-N group and the average weight of +1.0 times the standard deviation and divided into OR-N group. Observed the rats’general condition, diet changes, behavior (self-activity, mental status) changes, hair changes, weight of feed every day and body weight. Monitoring blood glucose and blood lipids situation is at 0, 4 and 8week. At 8 week, 8 rats of every group were killed randomly and collected specimens to detect liver index, serum ALT, AST, TC, TG and hepatic pathology.
Result The weight of O-N group was significantly higher than OR-N group and the normal control group. ALT and TG of O-N and OR-N group were significantly increased, while the O-N serum TC, TG was significantly higher than OR-N group; two groups of liver weight and liver index were significantly increased, O-N group liver weight and body weight were significantly higher than the OR-N group, but liver index no significant differences between. O-N and OR-N group hepatic lobules were structural damaged, hepatic cord disordered, hepatic sinusoid expansion and hepatocellular swelled obviously.
PartⅡdifference between obesity and obesity-resistant rats in non-alcoholic fatty liver
Objective To study the metabolic difference between obesity and obesity-resistant rats in non-alcoholic fatty liver.
Method 24 male Sprague-Dawley (SD) rats were separately from the control, O-N and OR-N group. In each group were randomly selected 8 rats, obesity tendency for ON group, obesity resistance for OR-N group and normal control group. At 8 week, the rats were fasted for 12h later, with 10% chloral hydrate anesthesia, taken blood, and determinate TC, TG, HDL, LDL, Leptin, Il-6, TNF-α, blood sugar and calculation of insulin sensitivity index. Observed the main organ, weigh adipose tissue pad around kidney and testicle and calculated body fat ratio. Keeping left perirenal adipose tissue in 10% formalin solution for adipose tissue pathology and preserving hypothalamus in liquid nitrogen for determinating NPY content.
Result O-N rats’the utilization rate of energy intake was significantly higher than OR-N group and the control group. The fat pad weight, FINS, ISI, Leptin and NPY content in the hypothalamus and serum of O-N group were significantly higher than the normal control group and the OR-N group, but body fat ratio between the two groups, TNF-α, IL-6, FBG and LDL were no significant difference. O-N group and OR-N rats’left perirenal fat cell diameter had significant increased and the volume become larger.
PartⅢUCP2 and PPARγ2 in obesity and obesity-resistant non-alcoholic fatty liver rats
Objective To study the UCP2 and PPARγ2 in obesity and obesity-resistant non-alcoholic fatty liver rats.
Method Using the two-step real-time fluorescence quantitative reverse transcription polymerase chain reaction to detect PPARγ2 and UCP2 mRNA expression in adipose and liver tissue.
Result UCP2 mRNA expression of OR-N group in liver and adipose tissue was significantly higher than O-N group and normal control group and the PPARγ2 mRNA expression in the adipose tissue was significantly lower than the control group. O-N group relative liver UCP2 mRNA expression was significantly lower than control group, the adipose tissue of PPARγ2 mRNA relative expression was significantly higher than both OR - N group and normal control group.
PartⅣthe effect ofβ-glucan and restoration of normal diet for obese and non-alcoholic fatty liver rats
Objective To study the effect ofβ-glucan and restoration of normal diet for obese and non-alcoholic fatty liver rats.
Method 56 male Sprague-Dawley (SD) rats were separately from the control, O-N and OR-N group. O-N and OR-N group were randomly divided into 3 groups of 8 only, namely ON-1 Group, ON-2 Group, ON-3 group and the OR-N-1 group, OR-N-2 group, OR-N-3 group; eight normal rats as control group. Control group eating normal diet; ON-1 and OR-N-1 group 500mg/kg.d-1β-glucan administered intervention; ON-2 and OR-N-2 group high-fat diet group sustained; ON-3 and OR-N-3 group returned to normal diet. After 4 weeks intervention, the rats were fasted for 12h later, with 10% chloral hydrate anesthesia, taken blood, and determinate TC, TG, HDL, LDL,ALT and AST. Observed the main organ, weigh adipose tissue pad around kidney and testicle and calculated body fat ratio. Keeping left liver tissue in 10% formalin solution for liver tissue pathology and preserving left liver tissue in liquid nitrogen for determinating SOD and MDA content.
Result O-N weight in each group was still significantly higher than the normal control group, OR-N-1 group and the OR-N-2 group body weight also significantly increased. O-N-2 group and the OR-N-2 rats body fat ratio was significantly increased; ON-1 group and the OR-N-1 group body fat ratio although still higher than the normal control group, but compared with the same group 2, both downward trend; ON-1 group and ON-3 rats compared with ON-2 group, body fat ratio decreased significantly, OR-N-3 rats compared with OR-N-2 group, body fat ratio decreased significantly. O-N-2 group of TC, TG, LDL significantly increased, while HDL significantly reduced, OR-N-2 group of TG, LDL significantly increased; and compared with O-N-2 group, O-N-1 group TC decreased significantly, O-N-3 Group TG significantly decreased, HDL increased significantly;and compared with OR-N-2 group, OR-N-1 group had a significant reduction in TG. O-N-2 Group ALT, liver index was significantly higher than the normal control group and O-N-3 group; OR-N-2 group ALT was significantly higher than the normal group and the OR-N-3 group, liver index was significantly higher than the normal group; each group no significant differences in AST. O-N-1 group and the OR-N-1 group SOD activity was significantly higher than the normal group, ON-2 group and the OR-N-2 group SOD activity was significantly lower than the normal group; MDA content of O-N-1 group and O-N-3 group was significantly lower than the O-N-2 group, OR-N-1 group was significantly lower than the OR-N-2 Group, O-N-2 group and the OR-N-2 group was significantly higher than the normal group.
Conclusions
1. Successfully create the obesity and obesity-resistant non-alcoholic fatty liver rat model with high-fat and high-energy feed
2. We found obesity and obesity-resistant non-alcoholic fatty liver rats has increased body fat ratio, glucose, TNF-α, IL-6 and dyslipidemia, the phenomenon of insulin resistance, dyslipidemia is the causes of non-alcoholic fatty liver.
3. Obesity resistance are probably happened because of visceral adipose tissue UCP2 mRNA expression levels increased and PPARγ2 mRNA expression was inhibited, reducing leptin resistance and insulin resistance, lowering NPY content, thereby reduced the energy intake and utilization rates, increased energy consumption and avoided the occurrence of obesity.
4. Liver tissue UCP2 mRNA expression levels significantly increased, and probably had more than the compensatory ability of the body and have an adverse impact on liver injury.
5. Return to normal diet or the intervention ofβ-glucan can inhibit weight gain in obese tend rats, reduce serum cholesterol and body fat content and improve nonalcoholic fatty liver.
6. Under the high-fat and high-energy diet-induced, the weight gain of obesity-resistant rats tend to start faster than obese rats, suggesting that long-term high-fat diet may lead to obesity-resistant rats fat.
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