Hepatic Fatty Acid Metabolism and Steatosis

描述（由申请方提供）：肝脂肪酸（FA）代谢和甘油三酯储存紊乱促进肝脂肪变性，被认为是非酒精性脂肪肝（NAFLD）的关键代谢前体。本申请将研究肝脏FA代谢的调节与三个重叠的遗传限制点的关系。这些包括FA区室化（L-FABP）、氧化利用（PPAR（））和甘油三酯（TG）输出动员（apoB 100）。三个关键概念构成了当前应用程序的基础。首先，我们已经产生了有针对性地删除肝脏脂肪酸结合蛋白（L-FABP）基因的小鼠，并证明了FA区室化和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区室化为TG池中的作用，TG池用于储存或分泌，以及L-FABP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。数据支持一种模型，其中多不饱和脂肪酸（PUFA）通过过氧化物酶体增殖物激活受体α（PPARalpha）直接前馈调节脂肪酸氧化，其下游靶点包括脂肪酸氧化基因和L-FABP。我们将研究L-FABP和PPARalpha在FA信号传导、肝脏脂肪生成和能量利用的综合调节中的遗传相互作用。我们将进一步研究一个共同的多态性（L162 V）在肝脏脂肪酸利用和TG代谢的PPARalpha基因的功能。肝脏TG代谢的第三个关键概念是载脂蛋白B100（apoB 100）在VLDL组装和分泌中的显性遗传作用。我们将进一步研究L-FABP，PPARalpha和apoB 100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运输的基本机制，并确定与NAFLD中肝脏脂质蓄积的分子发病机制相关的重要途径，NAFLD可能影响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.