SREBP-1c, a mediator of insulin action on hepatic gene expression

Abstract

Protein synthesis in mammalian cells is regulated through alterations in the states of phosphorylation of initiation and elongation factors (eIF's and eEF's), and of other regulatory proteins. This modulates their activities or their abilities to interact with one another. Insulin activates a number of these proteins including the guanine nucleotide-exchange factor eIF2B; the eIF4F complex, which (through eIF4E) interacts with the cap of the mRNA; p70 S6 kinase and elongation factor eEF2, which mediates the translation step of elongation. Control of the last three of these is linked to mTOR. In CHO cells, regulation of all these proteins by insulin is modulated by the presence of amino acids and/or glucose in the medium. For example, p70 S6 kinase activity declines in the absence of amino acids and cannot be stimulated by insulin under this condition. Readdition of amino acids, especially leucine, restores activity and insulin-sensitivity. In the case of eIF2B and eEF2, both amino acids and glucose must be provided in order for insulin to regulate their activities. In contrast, insulin-stirnulation of the formation of eIF4F complexes requires glucose, but not amino acids. Glucose metabolism is required for this permissive effect.Provision of substrates to mammalian tissues requires constant adaptations of metabolism to the quality and quantity of nutrients. Although it is well known that insulin has an important role in hepatic adaptations at the gene level, the molecular mechanisms involved are poorly understood. Recent findings have pointed to SREBP-lc (Sterol Regulatory Element Binding Protein -1c) as the transcription factor involved in insulin action. We have shown that SREBP-lc expression and nuclear abundance is positively regulated by insulin through a mechanism involving PL-kinase, and negatively by glucagon. Adenovirus-mediated ovcrexprcssion of a transcriptionally active form of SREBP-I c in cultured rat hepatocytes mimicks the inductive effects of insulin on glycolytic and lipogenic gene expression. A dominant negative form of SREBP-lc has the opposite effects. SREBP-lc mimicks also the negative effect of insulin since it is able to down-regulate the expression and the promoter activity of phosphoenolpyruvate carboxykinase in cultured hepatocytes. Injection of an adenovirus containing the active form of SREBP-lc to diabetic mice induces a rapid decrease of their hyperglycaemia and the predicted changes in hepatic gene expression. These studies point out to SREBP-lc as an important actor in the long term regulation of glucose homeostasis. ~1 7Insulin-Regulated Gene Expression.