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: 8131250
• 负责人: JACQUELYN J. MAHER
• 金额: $ 48.34万
• 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/8131250
• 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. PUBLIC HEALTH RELEVANCE: There is a strong belief that the modern American diet, which is enriched in both sugar and saturated fat, is responsible for many health problems including fatty liver disease. This research proposal is based on the hypothesis that sugar, rather than saturated fat, is the dietary nutrient with the greatest toxicity toward the liver. Interestingly, when sugar is eaten together with saturated fat, the combination is extraordinarily toxic to the liver. We believe this enhanced toxicity is not attributable to an additive effect of the two nutrients, but rather to the ability of saturated fat to enhance the toxicity of sugar. The goal of this project is to emphasize the pivotal role of dietary sugar as a mediator of fatty liver disease. We hope to use the information gained from the research to influence policymakers to take steps to reduce sugar consumption in the U.S.

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是美国肝病的主要原因，估计有2000万人显示出与脂肪有关的肝损伤的证据。自1970年以来，NAFLD的快速上升表明环境因素在疾病的发病机制中起着关键作用。流行病学研究指出，饮食中的糖是NAFLD的一个特定风险因素;糖可以通过从头脂肪生成（DNL）过程转化为有毒的长链饱和脂肪酸（SFA）来损害肝细胞。DNL不是SFA进入肝脏的唯一途径，但我们实验室的研究表明，DNL衍生的SFA特别具有肝毒性。相比之下，存在于饮食中的SFA在体内诱导相对较小的肝损伤。有趣的是，尽管与其他营养素一起喂养时它们显然无害，但膳食SFA可以与膳食糖协同作用，促进严重的脂肪肝疾病。形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质。因此，导致显著脂肪肝疾病的膳食营养素或营养素组合可能与其刺激DNL的能力直接相关。具体目标1将研究膳食饱和脂肪与膳食糖协同促进脂肪肝疾病的可能性，其不是通过直接促进细胞毒性SFA库，而是通过放大DNL和增加毒性DNL SFA的肝脏产生。实验还将解决这样的假设，即由于肝脏内的独特分配，膳食SFA本身的毒性低于DNL SFA。这些实验将利用小鼠脂肪肝的甲硫氨酸胆碱缺乏模型，已知其中肝损伤取决于DNL SFA的肝脏积累。膳食和DNL脂肪酸将通过独特的稳定同位素标记在体内通过几种代谢途径单独追踪。具体目标2将探索DNL导致肝细胞死亡的细胞事件。实验将证实肝细胞死亡与DNL直接相关，使用药理学和遗传学手段诱导DNL，并将靶向由DNL激活的各种细胞内信号传导途径，以确定哪些介导细胞死亡。具体目标3将检验DNL SFA不仅在喂食MCD的小鼠中，而且在饮食诱导肥胖的标准非MCD模型中是脂肪肝疾病的关键介质的假设。与MCD模型中一样，与DNL SFA相比，预计膳食SFA在膳食诱导的肝损伤发病机制中发挥的作用有限。该项目的最终目标是证明DNL对脂肪肝疾病的重要性，并以此类推，饮食糖和其他刺激DNL的营养物质的重要性。从这项研究中获得的信息将指导政策制定者制定营养指南，最大限度地减少过量的DNL。 公共卫生相关性：人们强烈认为，富含糖和饱和脂肪的现代美国饮食是导致包括脂肪肝在内的许多健康问题的原因。这项研究建议是基于这样的假设，即糖，而不是饱和脂肪，是对肝脏毒性最大的膳食营养素。有趣的是，当糖与饱和脂肪一起食用时，这种组合对肝脏的毒性非常大。我们认为这种增强的毒性不是归因于两种营养素的叠加效应，而是饱和脂肪增强糖毒性的能力。该项目的目标是强调膳食糖作为脂肪肝疾病媒介的关键作用。我们希望利用从研究中获得的信息来影响政策制定者采取措施减少美国的糖消费。