Long chain fatty acids and certain derivatives may perturb key cellular functions such as maintenance of calcium balance, mitochondrial oxidative phosphorylation, and cytochrome P-450- dependent biotransformation. These effects threaten cell homeostasis, especially under conditions in which cellular fatty acid abundance or flux is increased, yet their determinants are largely unknown, and protective mechanisms unidentified. Recent studies have called attention to extramitochondrial fatty acid oxidation, i.e. omega-oxidation in endoplasmic reticulum and beta-oxidation in peroxisomes, yet a specific role for these supplemental pathways has not been elucidated. Omega- Oxidation converts fatty acids to their dicarboxylic analogs. Long chain dicarboxylic acids, the further oxidation of which is largely peroxisomal, are potent uncouplers of mitochondrial oxidation phosphorylation and are present in serum and urine of subjects with Reye's and Zellweger syndromes, in which hepatic dysfunction is associated with impaired hepatic fatty acid oxidation. Omega-Oxidation, peroxisomes, and liver fatty acid binding protein (L-FABP) are induced by high fat diet, and by clofibrate and other peroxisome-proliferating agents. This parallel regulation implies a functional relationship among components of what may comprise an auxiliary (extramitochondrial) oxidation system which may serve to limit the abundance of fatty acids and derivatives in critical cell compartments. Despite their importance, these interactions remain to be defined and quantified. The experiments describe in this proposal emphasize three major areas: (1) characterization and quantification of extramitochondrial fatty acid oxidation, emphasizing interactions among mono- and dicarboxylic acids, omega-oxidation, peroxisomes, and FABP; (2) the relationship of these to effects of altered fatty acid metabolism on liver cytosolic (Ca2+), mitochondrial oxidative phosphorylation, and cytochrome P-450 spin state and activity; and (3) studies of human FABP, including immunochemical assay, and characterization of its function and regulation in Hep G2 cells. The studies will test the general hypothesis that extramitochondrial pathways interacting with FABP serve to mitigate disruptive effects of intracellular long chain fatty acids and certain derivatives. They will provide new insights into a fundamental aspect of cellular fatty acid metabolism, as well as its relationship to both normal cell function and to clinical liver diseases in which abnormal fatty acid metabolism appears to be of pathogenetic significance.
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