Fatty acid synthase (FAS) is an enzyme critical for de novo fatty acid synthesis. Glucose regulates human FAS expression by mediating FAS mRNA stability. Glucose also induces the binding of a 178 kD protein to the FAS message, suggesting that this protein links intermediary metabolism and fatty acid biosynthesis. This RNA binding protein has been purified and partially sequenced. Its major binding element has been identified. The studies in this application will test the hypothesis that this glucose-inducible protein regulates de novo fatty acid synthesis by mediating FAS gene expression.
The specific aims are: 1-To clone and express the 178 kD FAS mRNA binding protein. 2-To determine the binding activity of the 178 kD protein in different lipogenic tissues in the setting of experimental diabetes in mice. 3-To demonstrate the involvement of the 178 kD binding element in message stability. 4-To inactivate the 178 kD protein in HepG2 cells and determine effects on lipoprotein secretion and cell growth. 5-To overexpress the 178 kD protein in HepG2 cells and determine effects on lipoprotein secretion and cell growth. We have identified what appears to be a novel RNA binding protein. Characterizing this RNA binding protein could provide the basis for innovative therapies aimed at human disorders associated with abnormal fatty acid and glucose metabolism. These disorders include obesity, hyperlipidemia, non-insulin-dependent diabetes mellitus and even malignancies.
