Regulation of the gene for fatty acid synthase.

The activity of hepatic fatty acid synthase (EC 2.3.1.85) correlates positively with the rate of synthesis of long-chain fatty acids. Thus, in a starved chick, both the rate of fatty acid synthesis and the activity of fatty acid synthase are low. Feeding stimulates both processes. The increase in fatty acid synthase activity caused by feeding is due to an increase in the concentration of enzyme protein, which in turn is caused by an increase in the rate of synthesis of the enzyme. Using fatty acid synthase cDNA clones isolated in our laboratory, we showed that feeding causes a rapid increase in the level of fatty acid synthase mRNA. Increased transcription of the fatty acid synthase gene precedes the increase in fatty acid synthase mRNA level caused by feeding, which indicates regulation at the level of transcription. The feeding-induced stimulation of fatty acid synthase can be mimicked in culture by incubating chick embryo hepatocytes with insulin and thyroid hormone. Glucagon inhibits the increase caused by insulin and thyroid hormone. Enzyme synthesis is the regulated step. In hepatocytes in culture, thyroid hormone stimulates and glucagon inhibits the accumulation of fatty acid synthase mRNA. Insulin has only a small stimulatory effect on mRNA level despite a large stimulation of the synthesis of fatty acid synthase. Thus, thyroid hormone and glucagon regulate enzyme level at a pretranslational step, whereas insulin regulates the translation of fatty acid synthase mRNA. We conclude that complex hormonal regulation of the production and translation of fatty acid synthase mRNA underlies the dietary regulation of enzyme synthesis observed in intact animals. Future work will involve isolation of cloned genomic DNA for the fatty acid synthase gene and identification of nucleotide sequences involved in the regulation of this gene.