Regulation of hepatic gene expression is largely responsible for the control of nutrient metabolism. We previously showed that the transcription factor STAT3 regulates glucose homeostasis by suppressing the expression of gluconeogenic genes in the liver. However, the role of STAT3 in the control of lipid metabolism has remained unknown. We have now investigated the effects of hepatic overexpression of STAT3, achieved by adenovirus-mediated gene transfer, on glucose and lipid metabolism in insulin-resistant diabetic mice. Forced expression of STAT3 reduced blood glucose and plasma insulin concentrations as well as the hepatic abundance of mRNA for phosphoenolpyruvate carboxykinase. However, it also increased the plasma levels of triglyceride and total cholesterol without affecting those of low density lipoprotein–or high density lipoprotein–cholesterol. The hepatic abundance of mRNAs for fatty acid synthase and acetyl-CoA carboxylase, both of which catalyze the synthesis of fatty acids, was increased by overexpression of STAT3, whereas that of mRNAs for sterol regulatory element–binding proteins 1a, 1c, or 2 was unaffected. Moreover, the amount of mRNA for acyl-CoA oxidase, which contributes to β-oxidation, was decreased by forced expression of STAT3. These results indicate that forced activation of STAT3 signaling in the liver of insulin-resistant diabetic mice increased the circulating levels of atherogenic lipids through changes in the hepatic expression of genes involved in lipid metabolism. Furthermore, these alterations in hepatic gene expression likely occurred through a mechanism independent of sterol regulatory element–binding proteins.

The liver plays a key role in the regulation of nutrient metabolism in living animals. Such regulation is achieved by changes in the activity or abundance of enzymes that function in glucose or lipid metabolism (11, 14). Various transcription factors participate in control of the genes for such enzymes and thereby contribute to the regulation of nutrient metabolism. For example, forkhead transcription factor O1 (FOXO1) and cAMP-responsive element–binding protein are essential for induction of the genes for gluconeogenic enzymes