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.
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