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: 8443827
• 负责人: JACQUELYN J. MAHER
• 金额: $ 38.08万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443827
• 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; liver injury; 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(申请人提供)：非酒精性脂肪性肝病(NAFLD)是美国肝脏疾病的主要原因，估计有2000万人表现出与脂肪相关的肝脏损伤的证据。自1970年以来，NAFLD的迅速上升表明，环境因素在该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的特定危险因素；糖可通过新生脂肪生成(DNL)过程转化为有毒的长链饱和脂肪酸(SFA)，从而损害肝细胞。DNL并不是SFA进入肝脏的唯一途径，但我们实验室的研究表明，DNL来源的SFA具有特别的肝毒性。相比之下，饮食中存在的SFA在体内对肝脏的损伤相对较小。有趣的是，尽管膳食SFA在与其他营养素一起喂养时看起来是无害的，但膳食SFA可以与膳食糖协同作用，促进严重的脂肪肝。这一假设的基础是DNL SFA是NAFLD肝细胞损伤的主要介质。因此，导致严重脂肪肝的饮食营养素或营养素组合很可能与它们刺激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的可能性，不是通过直接促进细胞毒性SFA池，而是通过放大DNL和增加肝脏有毒DNL SFA的产生。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。这些实验将利用蛋氨酸-胆碱缺乏的小鼠脂肪肝模型，在该模型中，肝脏损伤取决于DNL SFA的肝脏积聚。膳食和DNL脂肪酸将通过体内几种代谢途径，通过标记独特的稳定同位素进行单独追踪。具体目标2将探讨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，通过药物和遗传手段诱导DNL，并将靶向于DNL激活的各种细胞内信号通路，以确定哪些信号通路介导细胞死亡。具体目标3将验证这样的假设，即DNL SFA不仅在MCD喂养的小鼠中是脂肪肝的关键介质，而且在饮食诱导的肥胖的标准的非MCD模型中也是如此。在MCD模型中，与DNL SFA相比，膳食SFA在饮食诱导的肝损伤发病机制中的作用有限。该项目的最终目标是证明DNL对脂肪肝疾病的重要性，以此类推，饮食中的糖和其他刺激DNL的营养素的重要性。从这项研究中获得的信息将指导决策者制定营养指南，将过量的DNL降至最低。