Extramitochondrial pathways of long chain fatty acid oxidation in liver (w-oxidation in the SER, and b-oxidation in peroxisomes) are important in the dispostion of fatty acids under conditions in which their availability in the hepatocyte exceeds the capacities of the normally predominant esterification and mitochondrial b-oxidation pathways. The extramitochondrial pathways, lacking the constraints which limit mitochondrial b-oxidation, may thusassume increased importance during ingestion of high fat diet, starvation, and uncontrolled diabetes mellitus, as well as under conditions in which the mitochondrial pathway is relatively impaired under the influence of metabolic regulation, pharmacological or toxic agents, or disease. While the extramitochrondrial pathways thus provide a mechanism by which the hepatocyte is able to adapt to an excess supply of fatty acids, they do so at a cost to the cell. Thus, w-oxidation results in the formation of long chain dicarboxylic fatty acids (DCA), which impair mitochondrial function, and peroxisomal b-oxidation generates hydrogen peroxide, and thusoxidative stress. In addition, recent studies by Kaikaus, Bass, et al. have shown that DCA are the proximate mediators of the inductive effects of peroxisome proliferators on these pathways, as well as serving as endogenous activator-ligands of the peroxisome proliferator-activated receptor (PPAR), a member of the nuclear hormone receptor superfamily, uponwhich mediation of the induction depends. As a result, increased extramitochondrial oxidation of fatty acids may lead to altered gene expression and to oxidant-induced cell injury and mutation, and may account for the carcinogenicity of peroxisome proliferators in rodents. Based on these and related considerations, we hypothesize that activity of the extramitochondrial pathways plays a significant role in the pathogenesis of certain acute and chronic liver diseases, including those associated with abnormalities of fatty acid metabolism or changes in growth regulation and tumorigenesis. Among the planned studies, we propose to use GCMS to identify and quantify DCA and other extramitochondrial oxidation pathway intermediates in serum, liver, and other materials obtained from patient subjects and from laboratory experiments involving liver cell fractions and cell culture, perfused rat liver, and whole animals. (Necessary institutional approvals have been granted.) We expect to define relationships between their abundance and rates of production/catabolism under various conditions, and changes in fatty acid metabolism and expression of relevant genes, as well as to assess their interaction with nutritional and metabolic state, drugs and toxins, and liver injury and regeneration.
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