Dietary factors in the pathogenesis of steatohepatitis

脂肪性肝炎发病机制中的饮食因素

• 批准号: 6816566
• 负责人: JACQUELYN J. MAHER
• 金额: $ 35.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816566
• 关键词: apoptosis; ceramides; choline; cysteine endopeptidases; dietary carbohydrates; dietary constituent; dietary lipid; enzyme inhibitors; enzyme linked immunosorbent assay; fatty acid biosynthesis; fatty liver; genetic susceptibility; genetically modified animals; hepatitis; laboratory mouse; liver cells; methionine; mitochondrial disease /disorder; nutrition related tag; nutritional epidemiology; pathologic process; peroxidation; saturated fatty acids; terminal nick end labeling; unsaturated fatty acids

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)：肝脏脂肪变性(脂肪肝)只在一小部分人中进展为脂肪性肝炎。导致病情恶化的危险因素尚不确定，但研究表明，在某些情况下，脂肪性肝炎与肝脏甘油三酯(TG)分泌缺陷有关。小鼠的肝脏甘油三酯分泌可以通过喂养不含蛋氨酸和胆碱的饮食(蛋氨酸胆碱缺乏；MCD)来阻止；当这样的配方与过量的蔗糖一起服用时，它会引发严重的脂肪性肝炎。我们实验室的初步数据表明，富含蔗糖的MCD配方会在体内引起肝细胞凋亡。这一现象让人联想到以前在其他器官中描述的“脂细胞凋亡”。在这一应用中，我们检验了一种假设，即饮食中的蔗糖引起易感小鼠的脂肪细胞凋亡并导致脂肪性肝炎。目的1旨在证实MCD小鼠肝脏中存在脂肪细胞凋亡，并证实膳食蔗糖在MCD脂肪性肝炎发病机制中的重要性。单独的实验将解决饮食蔗糖是否也诱导其他在肝脏甘油三酯分泌方面存在相关但独立缺陷(MTP缺陷；SCD-1缺陷)的小鼠的脂肪细胞凋亡。目的2探讨脂肪细胞凋亡与脂质过氧化在MCD脂肪性肝炎发病机制中的作用。尤其令人感兴趣的是，脂细胞凋亡和脂质过氧化是肝损伤的独立原因，还是脂细胞凋亡之后的脂质过氧化。目的3主要研究饱和脂肪酸诱导肝细胞凋亡的机制。实验将解决的问题是，脂肪酸毒性主要是由于神经酰胺的从头合成，还是由于线粒体的破坏而激活了细胞凋亡级联反应。总体而言，这项拟议的工作强调了脂肪细胞凋亡是肝脏甘油三酯分泌受损的个体中脂肪性肝炎的潜在重要原因。因为脂肪细胞的凋亡可以通过饮食营养来调节，所以一些有脂肪性肝炎风险的人也许能够通过改变饮食来降低他们的风险。