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: 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
• 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

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）仅在一小部分个体中进展为脂肪性肝炎。导致进展的风险因素尚不确定，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。通过喂食缺乏蛋氨酸和胆碱的饮食（蛋氨酸-胆碱缺乏; MCD）可以阻断小鼠的肝脏TG分泌;当这种配方与过量蔗糖一起给药时，会引起重度脂肪性肝炎。我们实验室的初步数据表明，富含蔗糖的MCD配方可导致体内肝细胞凋亡。这种现象让人想起以前在其他器官中描述的“脂凋亡”。在本申请中，我们检验了膳食蔗糖引起易感小鼠脂肪细胞凋亡并导致脂肪性肝炎的假设。目的1旨在证实脂肪细胞凋亡发生在MCD小鼠的肝脏中，并记录膳食蔗糖对MCD脂肪性肝炎发病机制的重要性。单独的实验将解决饮食蔗糖是否也诱导其他小鼠的脂肪细胞凋亡，这些小鼠具有相关但独立的肝脏TG分泌缺陷（MTP缺陷; Scd-1缺陷）。目的2探讨脂质过氧化反应中脂质凋亡在MCD脂肪性肝炎发病机制中的作用。特别感兴趣的是，是否脂凋亡和脂质过氧化是肝损伤或脂质过氧化后脂凋亡的独立原因。目的3探讨饱和脂肪酸诱导肝细胞凋亡的机制。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线粒体的破坏与细胞凋亡级联的激活。总体而言，拟议的工作突出了脂肪细胞凋亡作为一个潜在的重要原因，脂肪性肝炎的个人与受损的肝脏TG分泌。由于脂肪细胞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个体可以通过改变饮食来降低风险。