DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

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The quantity and type of dietary fat ingested contributes to health as well as the onset and progression of several chronic diseases. The liver plays a central role in whole body lipid synthesis and metabolism. Past studies conducted by the PI have focused on defining the molecular basis of fatty acid regulation of transcription of genes encoding proteins involved in fatty acid synthesis and oxidation. These studies have revealed 3 distinct mechanisms for fatty acid control of hepatic lipid metablosim: a) highly unsaturated n-3 fatty acids activate the peroxisome proliferator activated receptor (PPAR alpha) and induce the expression of genes involved in peroxisomal and microsomal fatty acid oxidation; b) n-3 and n-6 polyunsaturated fatty acids (PUFA) suppress the nuclear content of the sterol response element binding protein, SREBP1c. SREBP1c plays an important role in the control of lipid synthesis and storage; c) conversion of n-6 PUFA to prostanoids activated G-protein linked receptors in parenchymal cells and cultured adipocytes to suppress mRNAs encoding specific lipogenic genes. Of these 3 pathways, PUFA control of nuclear SREBP1c (nSREBP1c) level appears central to the regulation of hepatic lipid synthesis. However, the molecular basis for this control is not well understood. Moreover, studies show dysregulation of SREBP1c and microsomal fatty acid oxidation in livers of obese mice. Dietary fat control of nSREBP1c levels requires microsomal fatty acid oxidation is the hypothesis that will be tested. Changes in hormonal and/or nutrient intake accompanying obesity alter microsomal PUFA metabolism which impacts SREBP1c levels and contributes to the dysregulation of hepatic lipid metabolism. In this proposal,four aims are designed to answer the following questions: 1) How does SREBP1c functionally interact with nuclear receptors? 2) How does PUFA regulated hepatic SREBP1c levels? 3) Is microsomal fatty acid metabolism involved in regulating nSREBP1c abundance? 4) Is aberrant fatty acid metabolism associated with the dysregulation of nSREBP1c and lipogenic gene expression in livers of obese mice? Obesity is a growing human health issue worldwide and risk factor for chronic diseases, like hypertension, insulin resistance heart disease and cancer. PPAR alpha and SREBP1c are key hepatic transcription factors involved in partitioning lipid between synthesis/storage and oxidation. Understanding how these factors participate in this process in normal and obese animals will have important implications for human health.