Regulation of SREBP-1 expression and transcriptional action on HKII and FAS genes during fasting and refeeding in rat tissues

The sterol regulatory element binding protein 1 (SREBP-1) is regarded as a major factor involved in the nutritional regulation of lipogenesis. The aim of the present work was to demonstrate its involvement in the response of key genes of glucose and lipid metabolism in liver, adipose tissue, and skeletal muscle during fasting and refeeding. The regulation of hexokinase-2 (HKII) was investigated as a marker of the glucose metabolic pathway and that of FAS was investigated as a marker of the lipogenic pathway. The in vivo association of SREBP-1 with the promoter regions of these genes was determined in the different tissues using chromatin immunoprecipitation assays. Fasting decreased, and refeeding restored, FAS and HKII mRNA and protein levels in each tissue. The concomitant measurement of SREBP-1a and SREBP-1c mRNA levels, of mature SREBP-1 protein abundance in nuclear extracts, and of SREBP-1 interaction with target promoters led to the conclusion that SREBP-1 plays a major role in the response of FAS and HKII genes to nutritional regulation in rodents. These data elucidate the important role of SREBP-1 not only in the regulation of lipid metabolism but also of glucose metabolism and energy homeostasis.     

Long chain fatty acyl-CoA synthetase 5 expression is induced by insulin and glucose: involvement of sterol regulatory element-binding protein-1c

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.