METABOLIC REGULATION OF LIPID BIOGENESIS

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The LONG-TERM OBJECTIVES of this research are two fold: 1) to define the role of fatty acids in the regulation of the stearoyl-CoA desaturase genes in mouse liver and adipose tissue. 2) to understand the molecular mechanisms that control the expression of the mouse stearoyl-CoA desaturase genes in differentiating preadipocytes and fully developed adipocytes. As an approach to the first problem, I plan to continue my studies to the mechanisms that regulate the expression of the stearoyl-CoA desaturase genes in the liver and adipose tissue of mice that have been fed fat-free diets and diets containing either saturated or unsaturated fatty acids. To address the second problem, I plan to extend my initial studies on the regulatory mechanisms that occur during the differentiation of mouse 3T3-L1 preadipocytes into adipocytes in culture. The differentiation of 3T3-L1 preadipocytes into adipocytes in one of the few well characterized model systems available to study cellular differentiation at the molecular level. Stearoyl-CoA desaturase is a key enzyme in the biosynthesis of unsaturated fatty acids as well as the regulation of this process. I have cloned and determined the genetic organization of the two stearoyl-CoA desaturase gene (SCD1 and SCD2) both of which are transcriptionally activated during preadipocyte differentiation but are regulated differently by fatty acids in mouse liver, adipose and other tissues. The major aim of this proposal is to establish precisely how fatty acids control gene expression. Conventional molecular biology approaches will be used to help in answering the hypotheses. The SPECIFIC AIMS of the proposed research will be: 1) to identify and sequence the regulatory elements which control transcription of the two stearoyl-CoA desaturase gene during preadipocyte differentiation. 2) to identify the unique regulatory proteins which interact with the control elements of the genes, characterize them and determine their function. 3) to determine the site(s) at which fatty acids act to regulate the differential induction of the mouse liver and adipose stearoyl-CoA desaturase mRNAs, i.e. whether by affecting gene transcription or by changing the rate of specific mRNA turnover. The next objective will be to study the molecular mechanisms of this type of regulation. These studies may clarify molecular mechanisms of cellular differentiation and the new insight gained into the role of fatty acids in the regulation of gene activity in mammals may be useful in the treatment of heart disease.