Dietary factors in the pathogenesis of steatohepatitis

脂肪性肝炎发病机制中的饮食因素

基本信息

批准号：
7449514
负责人：
JACQUELYN J. MAHER
金额：
$ 33.08万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7449514
关键词：
Address Adult Apoptosis Benign Carbohydrates Cell Death Ceramides Choline Cirrhosis Condition Corn starch preparation Data Defect Diabetes Mellitus Diet Dietary Factors Dietary Fats Dietary Fats, Unsaturated Dietary Sucrose Disease Disruption Event Fatty Acids Fatty Liver Genetic Predisposition to Disease Genie Heart Hepatic Hepatocyte Hepatotoxicity Individual Inflammation Injury Laboratories Lead Link Lip structure Lipid Peroxidation Lipids Liver Liver Failure Liver Fibrosis Liver diseases Malignant neoplasm of liver Mediator of activation protein Methionine Mitochondria Modeling Monitor Mus Nutrient Obesity Organ Pancreas Pathogenesis Process Relative (related person)Reporting Research Risk Risk Factors Rodent Rodent Model Saturated Fatty Acids Series Standards of Weights and Measures Steatohepatitis Sucrose Testing Toxic effect Triglycerides Uncertainty Unsaturated Fatty Acids Week Work caspase-3 cell injury concept design feeding in vivo inhibitor/antagonist interest mitochondrial dysfunction novel research study saturated fat

项目摘要

DESCRIPTION (provided by applicant): Hepatic steatosis (fatty liver) progresses to steatohepatitis in only a small proportion of individuals. The risk factors that lead to progression are uncertain, but studies suggest that in some cases steatohepatitis is linked to a defect in hepatic triglyceride (TG) secretion. Hepatic TG secretion can be blocked in mice by feeding a diet devoid of methionine and choline (methionine-choline-deficient; MCD); when such a formula is administered together with excess sucrose, it provokes severe steatohepatitis. Preliminary data from our laboratory indicate that a sucrose-rich MCD formula causes hepatocellular apoptosis in vivo. This phenomenon is reminiscent of "lipoapoptosis" that has been described previously in other organs. In this application, we test the hypothesis that dietary sucrose provokes lipoapoptosis in susceptible mice and leads to steatohepatitis. Aim 1 is designed to confirm that lipoapoptosis takes place in the livers of MCD mice and document the importance of dietary sucrose to the pathogenesis of MCD steatohepatitis. Separate experiments will address whether dietary sucrose also induces lipoapoptosis in other mice that have related but independent defects in hepatic TG secretion (MTP-deficient; Scd-1-deficient). Aim 2 will investigate the importance of lipoapoptosis relative to lipid peroxidation in the pathogenesis of MCD steatohepatitis. Of particular interest is whether lipoapoptosis and lipid peroxidation are independent causes of liver injury or lipid peroxidation follows lipoapoptosis. Aim 3 concentrates on the mechanism by which saturated fatty acids cause hepatocyte apoptosis. Experiments will address whether fatty acid toxicity is due primarily to de novo synthesis of ceramide or to disruption of mitochondria with activation of an apoptosis cascade. Overall, the proposed work highlights lipoapoptosis as a potentially important cause of steatohepatitis in individuals with impaired hepatic TG secretion. Because lipoapoptosis can be regulated by dietary nutrients, some individuals at risk of steatohepatitis may be able to reduce their risk by modifying their diet.

描述（由申请人提供）：肝脂肪变性（脂肪肝）仅在一小部分个体中发展为脂肪性肝炎。导致进展的危险因素尚不确定，但研究表明，在某些情况下，脂肪性肝炎与肝甘油三酸酯（TG）分泌的缺陷有关。肝TG分泌可以通过喂食没有蛋氨酸和胆碱的饮食（蛋氨酸 - 胆碱缺乏； MCD）来阻断小鼠。当这样的配方与多余的蔗糖一起施用时，它会引起严重的脂肪性肝炎。来自我们实验室的初步数据表明，富含蔗糖的MCD公式在体内引起肝细胞凋亡。这种现象让人联想到其他器官中先前已经描述的“脂肪凋亡”。在此应用中，我们检验了以下假设：饮食中的蔗糖会促进易感小鼠的脂肪凋亡并导致脂肪性肝炎。 AIM 1旨在确认脂肪凋亡发生在MCD小鼠的肝脏中，并记录饮食中蔗糖对MCD脂肪性肝炎发病机理的重要性。单独的实验将解决饮食中蔗糖是否还会在其他与肝TG分泌相关但独立缺陷的小鼠（MTP缺陷型； SCD-1缺陷型）中诱导脂肪凋亡。 AIM 2将研究脂肪凋亡相对于脂质过氧化在MCD脂肪性肝炎发病机理中的重要性。特别令人感兴趣的是脂肪凋亡和脂质过氧化是肝凋亡后的独立原因还是脂质过氧化。 AIM 3集中在饱和脂肪酸引起肝细胞凋亡的机制上。实验将解决脂肪酸的毒性是主要是由于神经酰胺从头合成还是通过激活凋亡级联反应的线粒体破坏。总体而言，拟议的工作突出了脂肪凋亡是肝TG分泌受损的个体中脂肪性肝炎的潜在重要原因。由于脂肪凋亡可以通过饮食营养素来调节，因此一些有脂肪性肝炎风险的人可以通过改变饮食来降低风险。