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: 8299079
• 负责人: JACQUELYN J. MAHER
• 金额: $ 39.46万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299079
• 关键词: Address; American; Belief; Cell Death; Cessation of life; Choline; Clinical Research; Consumption; Development; Diet; Dietary Factors; Dietary Sugars; Disease; Eating; Elements; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Event; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genetic; Goals; Health; Hepatic; Hepatocyte; Hepatotoxicity; Human; Injury; Injury to Liver; Investigation; Label; Laboratories; Left; Link; Lipids; Liver; Liver diseases; Macronutrients Nutrition; Mediating; Mediator of activation protein; Metabolic Pathway; Methionine; Modeling; Mus; Nature; Nutrient; Obesity; One-Step dentin bonding system; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Process; Production; Research; Research Project Grants; Research Proposals; Risk; Risk Factors; Role; Route; Saturated Fatty Acids; Scheme; Signal Pathway; Source; Steatohepatitis; Testing; Toxic effect; base; cytotoxic; feeding; high risk; in vivo; intrahepatic; lipid biosynthesis; mouse model; non-alcoholic fatty liver; nutritional guideline; research study; saturated fat; stable isotope; sugar; theories

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the U.S., with an estimated 20 million people displaying evidence of fat-related liver injury. The rapid rise in NAFLD since 1970 suggests that environmental factors play a critical role in the pathogenesis of the disease. Epidemiologic studies point to dietary sugar as a specific risk factor for NAFLD; sugar can harm liver cells by being converted to toxic long- chain saturated fatty acids (SFA) through the process of de novo lipogenesis (DNL). DNL is not the only route by which SFA enter the liver, but studies from our laboratory suggest that DNL-derived SFA are particularly hepatotoxic. In contrast, SFA present in the diet induce relatively little liver injury in vivo. Interestingly, despite their apparently innocuous nature when fed with other nutrients, dietary SFA can synergize with dietary sugar to promote severe fatty liver disease. The hypothesis that forms the basis of this proposal is that DNL SFA are major mediators of hepatocellular injury in NAFLD. Accordingly, dietary nutrients or nutrient combinations that cause significant fatty liver disease likely do so in direct relationship to their ability to stimulate DNL. Specific Aim 1 will investigate the possibility that dietary saturated fat synergizes with dietary sugar to promote fatty liver disease not by contributing directly to a cytotoxic SFA pool, but instead by amplifying DNL and increasing hepatic production of toxic DNL SFA. Experiments will also address the hypothesis that dietary SFA are themselves less toxic than DNL SFA due to unique partitioning within the liver. These experiments will utilize the methionine-choline-deficient model of murine fatty liver disease, in which liver injury is known to depend upon the hepatic accumulation of DNL SFA. Dietary and DNL fatty acids will be individually traced through several metabolic pathways in vivo by labeling with unique stable isotopes. Specific Aim 2 will explore the cellular events by which DNL leads to hepatocyte death. Experiments will confirm that hepatocyte death is directly linked to DNL using pharmacologic and genetic means to induce DNL, and will target various intracellular signaling pathways activated by DNL to determine which ones mediate cell death. Specific Aim 3 will test the hypothesis that DNL SFA are pivotal mediators of fatty liver disease not only in the MCD-fed mouse, but also in a standard, non-MCD model of diet-induced obesity. As in the MCD model, dietary SFA are expected to play a limited role in the pathogenesis of diet-induced liver injury in comparison to DNL SFA. The ultimate goal of the project is to demonstrate the importance of DNL to fatty liver disease and by analogy, the importance of dietary sugar and other nutrients that stimulate DNL. The information gained from this research will guide policymakers to develop nutritional guidelines that minimize excess DNL.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）是美国肝病的主要原因，估计有2000万人表现出与脂肪有关的肝损伤的证据。自1970年以来，NAFLD的迅速上升表明，环境因素在疾病的发病机理中起着至关重要的作用。流行病学研究指出，饮食糖是NAFLD的特定危险因素。糖可以通过从头脂肪生成过程（DNL）转化为有毒的长链饱和脂肪酸（SFA），通过转化为有毒的长链饱和脂肪酸（SFA）来伤害肝细胞。 DNL不是SFA进入肝脏的唯一途径，但是我们实验室的研究表明，DNL衍生的SFA尤其是肝毒性。相比之下，饮食中存在的SFA诱导体内相对较小的肝损伤。有趣的是，尽管饮食中的饮食SFA可以与饮食中的糖协同促进严重的脂肪肝病。构成该提议的基础的假设是DNL SFA是NAFLD中肝细胞损伤的主要介体。因此，引起严重脂肪肝病的饮食营养或营养组合可能与刺激DNL的能力直接关系。具体目标1将调查饮食中饱和脂肪与饮食糖协同促进脂肪肝病的可能性，而不是直接导致细胞毒性SFA池，而是通过扩增DNL并增加肝DNL SFA的肝产生。实验还将解决以下假设：由于肝脏中的独特分配，饮食中的SFA本身比DNL SFA毒性低。这些实验将利用鼠脂肪肝病的蛋氨酸 - 胆碱缺陷模型，其中已知肝损伤取决于DNL SFA的肝积累。通过用独特的稳定同位素标记，饮食和DNL脂肪酸将通过体内几种代谢途径进行单独追踪。具体目标2将探索DNL导致肝细胞死亡的细胞事件。实验将确认使用药物和遗传手段直接将肝细胞死亡与DNL联系起来，以诱导DNL，并将针对DNL激活的各种细胞内信号通路，以确定哪些途径介导了细胞死亡。具体的目标3将检验以下假设：DNL SFA不仅是MCD喂养的小鼠中的脂肪肝病的关键介质，而且还以饮食诱导的肥胖症的标准非MCD模型。与MCD模型一样，与DNL SFA相比，饮食SFA预计在饮食诱导的肝损伤的发病机理中起有限的作用。该项目的最终目的是证明DNL对脂肪肝病的重要性，并以类比的形式，饮食糖和其他刺激DNL的营养的重要性。从这项研究中获得的信息将指导决策者制定营养指南，以最大程度地减少DNL的过多。