Although long chain free fatty acids are an important energy substrate utilized by cardiac cells, it is unclear how these hydrophobic molecules enter cells. The purpose of this investigation is to define the mechanism of fatty acid uptake in myocardium. In an attempt to elucidate the molecular mechanism of efficient tissue- specific fatty acid uptake, known genes encoding intracellular proteins which interact with free fatty acids will be over-expressed in cells which do not significantly metabolize long chain free fatty acids. If fatty acid interactions with such a protein are required and sufficient for fatty acid uptake, over-expression will confer on cells the ability to internalize fatty acids. If these candidate proteins do not enable fatty acid uptake, then the method of expression cloning will be used to isolate a gene encoding a postulated plasma membrane fatty acid transport protein from rat ventricular myocytes. The gene will be characterized, the structure and functional domains of the protein will be defined. Subsequently, the expression of the protein involved in fatty acid transport will be examined in animal models of ischemic heart disease and cardiac hypertrophy. Transport of energy substrates into cells is a process through which metabolism of the substrate may be regulated. Furthermore, the ability of cardiac cells to internalize and use long chain free fatty acids as an energy substrate is modified by ischemia and varying mechanical workloads. Elucidation of the mechanism of uptake of fatty acids is an important step toward understanding the heart's ability to use this energy substrate under normal conditions. Moreover, definition of the molecular mechanism of fatty acid uptake into cells may provide further insights into cellular alterations in cardiac ischemia and hypertrophy.
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