DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

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DESCRIPTION (provided by applicant): The molecular basis of dietary fatty acid regulation of gene expression has gained considerable attention in recent years because of its contribution to chronic disease [obesity, diabetes & atherosclerosis]: Our studies have focused on dietary polyunsaturated fatty acid (PUFA: eicosapentaenoic acid [20:5n3] and docosahexaneoic acid [22:6n3]) control of three hepatic transcription factors, sterol regulatory element binding protein (SREBP-1c), peroxisome proliferator activated receptor (PPARalpha) and liver X receptor (LXRalpha). These studies have revealed new information on: a) dynamic & cell-specific PUFA regulation of each transcription factor; b) developmental regulation of SREBP-1c and its regulatory network, and c) a role for PPARalpha and SREBP-1 in PUFA synthesis; d) the regulation of fatty acid elongases & desaturases; e) induction of these enzymes generates fatty acids that do not normally accumulate in cells; these rare fatty acids impact cell signaling by affecting eicosanoid production. These findings have broad implications for metabolic regulation, particularly with regard to chronic diseases like diabetes, obesity and atherosclerosis, where clinical data links fatty acid metabolites to disease progression. There remains a poor understanding of the role fatty acid elongases play in hepatic and whole body physiology. We hypothesize that hepatic fatty acid elongation: a) regulates hepatic & extrahepatic (aortic and blood) fatty acid composition; b)/egulates key transcription factors [PPARalpha & SREBP-1 c]; and c) influences the onset or progression of chronic disease, e.g., diabetes, obesity or atherosclerosis. The specific aims are to: 1. Define the metabolic regulation of hepatic fatty acid elongases; 2. Define the role of PPARalpha and SREBP-1 in the regulation of fatty acid elongases; 3. Define the effects of fatty acid elongases on hepatocyte lipid composition and gene expression; 4. Determine how over expression of specific fatty acid elongases affects hepatic function, blood lipid composition and the onset of chronic disease.