Hepatic Fatty Acid Metabolism and Steatosis

肝脏脂肪酸代谢和脂肪变性

• 批准号: 7861167
• 负责人: Nicholas O. Davidson
• 金额: $ 3.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7861167
• 关键词: Address; Agonist; Animals; Area; Data; Defect; Development; Diet; Dominant Genetic Conditions; Down-Regulation; Elements; Exhibits; Fasting; Fatty Acid-Binding Protein 1; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Feedback; Fibrates; Genes; Genetic; Genetic Polymorphism; Hepatic; Human; In Vitro; Injury; Ligands; Lipids; Lipoproteins; Liver diseases; Mediating; Medium chain fatty acid; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Mutation; Obesity; PPAR alpha; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Polyunsaturated Fatty Acids; Population; Post-Translational Regulation; Predisposition; Production; Regulation; Reporter; Research Personnel; Role; Series; Serum; Signal Transduction; Steatohepatitis; Supplementation; Triglyceride Metabolism; Triglycerides; Very low density lipoprotein; Wild Type Mouse; apolipoprotein B-100; fatty acid metabolism; fatty acid oxidation; feeding; gain of function; in vivo; lipid biosynthesis; mutant; non-alcoholic fatty liver; oxidation; programs; receptor; response; trafficking; uptake

DESCRIPTION (provided by applicant): Disturbances in hepatic fatty acid (FA) metabolism and triglyceride storage promote hepatic steatosis, and are considered key metabolic precursors to nonalcoholic fatty liver disease (NAFLD). This application will examine the regulation of hepatic FA metabolism in relation to three overlapping genetic restriction points. These include FA compartmentalization (L-FABP), utilization for oxidation (PPAR() and triglyceride (TG) mobilization for export (apoB100). Three key concepts underlie the current application. First, we have generated mice with a targeted deletion of the liver fatty acid binding protein (L-FABP) gene and have demonstrated conditional defects in FA compartmentalization and delivery for beta-oxidation, TG synthesis and secretion. We will examine the role of L-FABP in hepatic FA compartmentalization into TG pools destined either for storage or for secretion and its role in modulating lipogenesis and lipotoxic injury. A second key concept is the regulation of hepatic lipogenesis through the alterations in FA flux. Data support a model in which polyunsaturated FA (PUFA) direct feed-forward regulation of FA oxidation via peroxisome proliferator activated receptor alpha (PPARalpha), downstream targets for which include FA oxidation genes and L-FABP. We will examine the genetic interactions of L-FABP and PPARalpha in the integrated regulation of FA signaling, hepatic lipogenesis and energy utilization. We will further examine the function of a common polymorphism (L162V) in the PPARalpha gene in hepatic FA utilization and TG metabolism. The third key concept in hepatic TG metabolism is the dominant genetic role of apolipoproteinB100 (apoB100) in VLDL assembly and secretion. We will further examine genetic interactions between L-FABP, PPARalpha and apoB100 in the regulation of hepatic VLDL assembly and secretion. These studies will address fundamental mechanisms involved in FA trafficking and define important pathways relevant to the molecular pathogenesis of hepatic lipid accumulation in NAFLD, a condition that likely afflicts a quarter of the US population.

描述(由申请人提供)：肝脏脂肪酸(FA)代谢紊乱和甘油三酯储存障碍会促进肝脏脂肪变性，被认为是非酒精性脂肪性肝病(NAFLD)的关键代谢前驱疾病。这项应用将检查与三个重叠的遗传限制点有关的肝脏FA代谢的调节。这些包括脂肪酸区划(L-FABP)、用于氧化的利用(PPAR())和动员甘油三酯(TG)用于出口(ApoB100)。三个关键概念构成了当前应用程序的基础。首先，我们建立了肝脏脂肪酸结合蛋白(L-FABP)基因定向缺失的小鼠，并证明在脂肪酸区划和传递β-氧化、甘油三酯合成和分泌方面存在条件性缺陷。我们将研究L-FABP在肝脏FA分解成供储存或分泌的TG池中的作用，以及它在调节脂肪生成和脂毒性损伤中的作用。第二个关键概念是通过改变FA流量来调节肝脏脂肪生成。数据支持多不饱和脂肪酸(PUFA)通过过氧化物酶体增殖物激活受体α(PPARpha)直接前馈调节FA氧化的模型，其下游靶标包括FA氧化基因和L FABP。我们将研究L-FABP和PPARα在FA信号、肝脏脂肪形成和能量利用的整合调控中的遗传交互作用。我们将进一步研究PPARpha基因的一个常见多态(L162V)在肝脏FA利用和TG代谢中的作用。肝脏TG代谢的第三个关键概念是载脂蛋白B100(ApoB100)在极低密度脂蛋白(VLDL)组装和分泌中的主导遗传作用。我们将进一步研究L-FABP、PPARα和载脂蛋白B100在调节肝脏极低密度脂蛋白组装和分泌中的遗传相互作用。这些研究将解决涉及FA运输的基本机制，并确定与NAFLD肝脂堆积的分子发病机制相关的重要途径，NAFLD可能会困扰四分之一的美国人口。