Previous studies have focused on the characterization of the in vivo function of sterol regulatory element-binding proteins (SREBPs), a family of transcription factors discovered by Brown and Goldstein that regulates cholesterol and fatty acid synthesis. SREBPs belong to the basic helix-loop-helix leucine zipper (b-HLH) family of transcription factors. Mammalian cells have three SREBP isoforms, designated SREBP-1a, SREBP-1c, and SREBP-2. Using oligonucleotide microarrays, we demonstrated that the SREBP-1 isoforms transcriptionally activate all enzymes required for the synthesis of monounsaturated fatty acids (Figure 1). These studies established SREBP-1 as the major transcriptional regulator of lipogenesis.

The hormonal regulator of lipogenesis in liver is insulin. We investigated whether there was a direct link between the action of insulin and SREBP-1c regulation in vivo by studying SREBP-1c regulation in livers of fasted and refed mice. Fasting reduces plasma concentrations of insulin and glucose whereas refeeding a high carbohydrate diet increases plasma insulin and glucose levels. In livers of fasted mice, the amount of SREBP-1c was reduced. Refeeding markedly increased SREBP-1c levels above nonfasted levels. The hepatic mRNAs for the fatty acid biosynthetic enzymes also increased 5-10-fold above nonfasted levels. These results provided evidence that SREBP-1c may be regulated by insulin or glucose and that SREBP-1c may mediate the well-described insulin-induced increase in hepatic fatty acid synthesis. Subsequent studies in primary hepatocytes and in streptozotocin-treated rats confirmed that insulin was the transcriptional activator of SREBP-1c expression. As such, SREBP-1c is the first identified transcriptional mediator of insulin action.