Mitochondrial enzymes play essential roles in energy production and transduction in many tissues, but are key in intermediary metabolism, especially of fatty acids, in the liver and intestine. Long chain acyl CoA dehydrogenase (LCAD) catalyzes the first step in the Beta-oxidation of long chain fatty acids in the mitochondrial matrix. Deficiency of this enzyme has recently been recognized to cause Reye's syndrome, sudden infant death, and cardiomyopathy. We will employ molecular and cellular biologic techniques to pursue the following goals: i) elucidation of the regulation of expression of the LCAD gene in liver, intestine and other tissues during development, with variations in diet, and in disease states; ii) analysis of changes in LCAD gene expression in cultured human liver and intestinal cells with alterations in nutrient supply; and iii) determination of the molecular basis of LCAD deficiency in humans.
The specific aims of this proposal include the isolation and characterization of human and rat LCAD CDNAS and the human gene, analysis of LCAD MRNA steady state levels in rat and human tissues, isolation and characterization of LCAD genomic regulatory elements responsive to changes in diet, delineation of the structure of human LCAD protein through crystallography and x-ray diffraction, and isolation of the mutations in human LCAD deficiency. These studies will increase understanding of gene expression and regulation, especially as this occurs for mitochondrial proteins encoded on the nuclear genome, and of the effects of altered fatty acid metabolism on liver and intestinal function, both in healthy and diseased states.
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