Two structurally and immunologically distinct fatty acid binding proteins have been purified from the cytosol of liver and small intestine. One of these proteins occurs abundantly in liver (hFABP, 14,184 Da) and is also present in substantial quantities in small intestinal epithelium together with equivalent quantities of a distinct intestinal FABP (gFABP, 15,063 Da). A third Mr 12,000 FABP found in myocardium appears to be distinct from both hFABP and gFABP. In addition, hFABP exists as four immunologically identical isoforms in liver, which show marked differences in bound endogenous fatty acids, including arachidonic acid. Regulation of hFABP by sex steroid hormones and hypo-lipidemic drugs is secondary to changes in hFABP mRNA; a role for fatty acids in mediating this regulation has been suggested by studies showing that they too may modulate hFABP concentration.
The aims of this proposal are two-fold: 1) To elucidate the intracellular function of the FABPs with emphasis on their possible role in the intracellular compartmentation of fatty acids. Toward this end, experiments are propossed which will study the fatty acid binding properties of the pure FABPs using an in vitro competitive binding assay, as well as the partition of fatty acids between the two intestinal FABPs following in vivo administration. The possibility that the FABPs differentially direct fatty acids towards different pathways of utilization will be tested by examining the effects of the pure proteins on the activity of enzymes and pathways of fatty acid utilization in vitro. 2) To further elucidate the mechanism whereby hFABP is regulated by hormonal, pharmacological and dietary factors by testing the hypothesis that fatty acids may mediate this regulation. The modulation of hFABP concentration and mRNA accumulation in liver and intestine as a function of dietary fat content and composition will be studied toward this end will be followed by studies of the influence of fatty acids on hFABP concentration and synthesis in hepatocyte monolayer cultures. The proposed studies will add substantial new information regarding the function and regulation of the FABPs, and will thus provide new insight into their role in the cellular regulation in lipid metabolism.
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