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: 7079445
• 负责人: JACQUELYN J. MAHER
• 金额: $ 34.77万
• 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/7079445
• 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）：只有一小部分人的肝脏脂肪变性（脂肪肝）会发展为脂肪性肝炎。导致疾病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酯 (TG) 分泌缺陷有关。通过喂食不含蛋氨酸和胆碱的饮食（蛋氨酸胆碱缺乏症；MCD），可以阻断小鼠的肝脏 TG 分泌；当这种配方与过量的蔗糖一起服用时，会引起严重的脂肪性肝炎。我们实验室的初步数据表明，富含蔗糖的 MCD 配方会导致体内肝细胞凋亡。这种现象让人想起之前在其他器官中描述的“脂肪凋亡”。在此应用中，我们测试了这样的假设：膳食蔗糖会引起易感小鼠的脂肪细胞凋亡并导致脂肪性肝炎。目标 1 旨在确认 MCD 小鼠肝脏中发生脂肪凋亡，并证明膳食蔗糖对 MCD 脂肪性肝炎发病机制的重要性。单独的实验将探讨膳食蔗糖是否也会诱导其他肝脏 TG 分泌缺陷（MTP 缺陷；Scd-1 缺陷）相关但独立缺陷的小鼠的脂肪凋亡。目标 2 将研究脂肪细胞凋亡相对于脂质过氧化在 MCD 脂肪性肝炎发病机制中的重要性。特别令人感兴趣的是脂肪细胞凋亡和脂质过氧化是否是肝损伤的独立原因，或者脂质过氧化发生在脂肪细胞凋亡之后。目标 3 重点研究饱和脂肪酸引起肝细胞凋亡的机制。实验将解决脂肪酸毒性是否主要是由于神经酰胺的从头合成或由于细胞凋亡级联激活而破坏线粒体所致。总体而言，拟议的工作强调脂肪细胞凋亡是肝脏 TG 分泌受损的个体脂肪性肝炎的潜在重要原因。由于脂肪细胞凋亡可以通过膳食营养素来调节，因此一些有脂肪性肝炎风险的个体可以通过改变饮食来降低风险。