Fatty Acid Binding Proteins-Ligand Specificity

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DESCRIPTION (provided by applicant): Long chain fatty acids (LCFAs) and LCFA-CoAs serve as important metabolic intermediates in lipid metabolism and as ligand regulators of nuclear transcription factors (PPARalpha, HNF4alpha) involved in LCFA, lipoprotein, and/or glucose metabolism. Although studies with purified fatty acid binding proteins (FABPs) in vitro and/or with overexpressed, transformed cells in culture suggest functions in LCFA metabolism, physiological roles of individual FABPs in vivo are unresolved. Liver cells (hepatocytes) express three proteins in abundance that bind both LCFAs and LCFA-CoAs: liver fatty acid-binding protein (L-FABP), sterol carrier protein-2 (SCP-2), and sterol carrier protein-x (SCP-x). The objective of this application is to: (i) eliminate synthesis of LCFA/LCFA-CoA binding proteins individually, and where indicated, multiply in gene-ablated mice; (ii) examine individual role(s) of these proteins in metabolism of straight- and branched-chain LCFAs in cultured hepatocytes and in vivo; and (iii) examine two potential nuclear regulatory mechanism(s) whereby the LCFA/LCFA-CoA binding proteins may exert effects. The specific aims are focused on cultured hepatocyes and gene-targeted mice to examine: Aim 1. LCFA uptake and intracellular LCFA/LCFA-CoA transport in hepatocytes cultured from gene-ablated mice and in vivo. Aim 2. Trafficking of L-FABP, LCFAs/LCFA-CoAs to nuclei, distribution within nuclei, and interaction with PPARalpha and HNF4alpha in cultured hepatocytes from control and gene-ablated mice. Aim 3. Oxidation of LCFAs in mitochondria, peroxisomes, and endoplasmic reticulum of cultured hepatocytes from gene-ablated mice and in vivo. Aim 4. Esterification for storage or secretion in cultured hepatocytes from gene-ablated mice and in vivo. With the growing awareness of interrelationships between intracellular fatty acid and glucose metabolism, results from these studies will contribute to our understanding of factors involved in diabetes as well as diseases of lipid metabolism, including atherosclerosis, obesity, and heart disease.