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In a screen for sterol regulatory element-binding protein (SREBP)-1c target genes in the liver, we identified long chain fatty acyl-CoA synthetase 5 (ACS-5). Hepatic ACS-5 mRNA is poorly expressed during fasting and diabetes and strongly induced by carbohydrate refeeding and insulin treatment. In cultured hepatocytes, insulin and a high glucose concentration induce ACS-5 mRNA. Adenoviral overexpression of a nuclear form of SREBP-1c in liver of diabetic mice or in cultured hepatocytes mimics the effect of insulin to induce ACS-5. By contrast, a dominant negative form of SREBP-1c abolishes the effect of insulin on ACS-5 expression. The dietary and SREBP-1c-mediated insulin regulation of ACS-5 expression indicate that ACS-5 is involved in the anabolic fate of fatty acids.

International audience; In vitro, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) mimics the positive effects of insulin on hepatic genes involved in glucose utilization, such as glucokinase (GK) and enzymes of the lipogenic pathway, suggesting that it is a key factor in the control of hepatic glucose metabolism. Decreased glucose utilization and increased glucose production by the liver play an important role in the development of the hyperglycemia in diabetic states. We thus reasoned that if SREBP-1c is indeed a mediator of hepatic insulin action, a hepatic targeted overexpression of SREBP-1c should greatly improve glucose homeostasis in diabetic mice. This was achieved by injecting streptozotocin-induced diabetic mice with a recombinant adenovirus containing the cDNA of the mature, transcriptionally active form of SREBP-1c. We show here that overexpressing SREBP-1c specifically in the liver of diabetic mice induces GK and lipogenic enzyme gene expression and represses the expression of phosphoenolpyruvate carboxykinase, a key enzyme of the gluconeogenic pathway. This in turn increases glycogen and triglyceride hepatic content and leads to a marked decrease in hyperglycemia in diabetic mice. We conclude that SREBP-1c has a major role in vivo in the long-term control of glucose homeostasis by insulin.

International audience; We have assessed the potential role of sterol regulatory element-binding protein-1c (SREBP-1c) on the transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC ) (PEPCK-C). SREBP-1c introduced into primary hepatocytes with an adenovirus vector caused a total loss of PEPCK-C mRNA and a marked induction of fatty acid synthase mRNA that directly coincided with the appearance of SREBP-1c in the hepatocytes. It also blocked the induction of PEPCK-C mRNA by cAMP and dexamethasone in these cells. In contrast, a dominant negative form of SREBP-1c (dnSREBP-1c) stimulated the accumulation of PEPCK-C mRNA in these cells. SREBP-1c completely blocked the induction of PEPCK-C gene transcription by the catalytic subunit of protein kinase A (PKA), and increasing concentrations of dnSREBP-1c reversed the negative effect of insulin on transcription from the PEPCK-C gene promoter in WT-IR cells. The more than 10-fold induction of PKA-stimulated PEPCK-C gene transcription caused by the co-activator CBP, was also blocked by SREBP-1c. In addition, dnSREBP-1c reversed the strong negative effect of E1A and NF1 on PKA-stimulated transcription from the PEPCK-C gene promoter. An analysis of the possible site of action of SREBP-1c using stepwise truncations of the PEPCK-C gene promoter indicated that the negative effect of SREBP-1c on transcription is exerted at a site between -355 and -277. We conclude that SREBP-1c is an intermediate in the action of insulin on PEPCK-C gene transcription in the liver and acts by blocking the stimulatory effect cAMP that is mediated via an interaction with cAMP-binding protein.