Coordinate Regulation of Rat Liver Genes by Thyroid Hormone and Dietary Carbohydrate a

The expression of many gene products in the liver is coordinately regulated by thyroid hormones and dietary carbohydrate. For example, hepatic malic enzyme in the rat is induced by either injection of 3,5,3'-triiodo-~-thyronine (T,) or feeding of a high-carbohydrate, fat-free (CHO) diet.' The regulation by these two stimuli is exerted at a pretranslational level?v3 Studies on isolated primary rat hepatocytes in culture indicate that both T, and glucose can act directly at the hepatocellular level to stimulate malic enzyme synthesis! An examination of approximately 230 hepatic mRNA species by cell-free translation and two-dimensional gel electrophoresis has revealed an extensive degree of overlap between the T,and CHO-diet-responsive domain^."^ Thus, switching rats from a standard chow diet to a CHO diet led to alterations in the relative levels of 10 mRNA translational products. All but one of these mRNA species also responded to elevated plasma T3 levels, and in each case the direction of change (that is, positive or negative) was the same. Because both elevated T3 and the CHO diet result in increased fatty acid synthesis, it is possible that a subset of these mRNA products, like malic enzyme, are involved in adaptive hyperlipogenesis. These products provide an interesting system to study coordinate gene regulation by hormonal and nutritional stimuli. In the past few years, we have focused on the regulation of one of these hepatic gene products, designated spot 14. Spot 14 was first identified by the nature of its translational product, which has an M, of 17 OOO and a PI of about 4.9.6 The expression of the spot 14 gene was of particular interest due to its rapid kinetics of induction. Following a single injection of T, into hypothyroid rats, spot 14 mRNA levels increased with a lag time between 10 and 20 min.' A similar lag time was observed following the intragastric administration of sucrose to normal rats? In cultures of primary hepatocytes, spot 14 mRNA levels are increased by addition of T, to the media? The rapidity of the response of this gene product suggests that it may be responding as a primary event to the hormonal or nutritional stimuli.