Fatty acid transport and its regulation

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We have cloned and characterized five mammalian fatty acid transport proteins (FATPs). FATP1 is expressed at high levels in heart, adipocytes, muscle, and brain. FATP4 is expressed predominantly in the brush border of the absorptive small intensive epithelial cells and is essential for uptake of LCFAs. Human FATP6 is expressed exclusively in heart muscle and its level is elevated in hypertrophic tissue. Our overall goal is to understand the molecular mechanism of fatty acid transport and its regulation. We focus on the FATPs as well as other proteins implicated in fatty acid transport: the "scavenger" receptors CD36 and SRI-BI; LACS (long chain fatty acyl CoA synthetase); and cytosolic FABPs (fatty acid binding proteins), and their roles in fatty acid transport in heart, adipocytes, and intestinal epithelial cells. Our specific aims are to 1) Determine whether these proteins functional synergize to enhance the transports of LCFAs by cultured cells and whether, depending on the transport mechanism involved, fatty acids are esterified to CoA upon entry. 2) Determine whether stable physical interactions occur between various FATPs, FABPs, SR-BI/CD36, and LACS. 3) Determine by antisense experiments which protein is rate-limiting for adipocyte LCFA uptake, both in the absence and presence of insulin. 4) Determine how insulin stimulates and TNF-alpha inhibits LCFA uptake by adipocytes 5) Clone and study the putative purine homologue of the cardiac-specific human FATP6. 6) Depending on the results obtained, use expression model systems to test the roles of FATP1, FATP4, and other proteins in LCFA uptake and determine the role of these proteins in whole-mouse lipid metabolism. Thus we will 1) Determine the expression pattern of these candidate fatty acid transport proteins within the developing and adult murine heart. 2) Using both FATP1 knockout and transgenic FATP1 over-expressing mice, determine the role of FATP1 in LCFA, uptake and lipid metabolism by adipose tissue and heart and striated muscle. 3) Using gene knock-out mice, determine the role of FAT4, SR- BI, and CD36 in uptake of LCFAs from the small intestine by the absorptive epithelial cells.