Hepatic Fatty Acid Metabolism and Steatosis

描述（由申请人提供）：肝脂肪酸（FA）代谢和甘油三酯储存紊乱可促进肝脂肪变性，被认为是非酒精性脂肪性肝病（NAFLD）的关键代谢前体。本应用程序将检查肝脏FA代谢的调节与三个重叠的遗传限制点有关。其中包括FA区隔化（L-FABP），氧化利用(PPAR（）和甘油三酯（TG）动员出口（apoB100）。当前应用程序的基础是三个关键概念。首先，我们培养了肝脏脂肪酸结合蛋白（L-FABP）基因靶向缺失的小鼠，并证明了FA区室化和传递β -氧化、TG合成和分泌的条件缺陷。我们将研究L-FABP在肝脏FA划分为储存或分泌的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FA通量的改变来调节肝脏脂肪生成。数据支持一种模型，即多不饱和脂肪酸（PUFA）通过过氧化物酶体增殖物激活受体α (ppar α)直接前馈调节脂肪酸氧化，下游靶点包括脂肪酸氧化基因和L-FABP。我们将研究L-FABP和ppar - α在FA信号、肝脏脂肪生成和能量利用的综合调控中的遗传相互作用。我们将进一步研究pparα基因中一种常见多态性（L162V）在肝脏FA利用和TG代谢中的功能。肝脏TG代谢的第三个关键概念是载脂蛋白b100 （apoB100）在VLDL组装和分泌中的主导遗传作用。我们将进一步研究L-FABP、ppar和apoB100在调节肝脏VLDL组装和分泌中的遗传相互作用。这些研究将解决涉及FA贩运的基本机制，并确定与NAFLD中肝脏脂质积累的分子发病机制相关的重要途径，NAFLD可能折磨着四分之一的美国人口。

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.