Insulin‐dependent and ‐independent regulation of sterol regulatory element‐binding protein‐1c

Insulin resistance, a state of reduced responsiveness to insulin, is associated with obesity and is the major pathogenic indicator of metabolic syndrome. Although major advances have been made in unraveling the underlying defects that cause insulin resistance, many of the pathways and regulators that connect insulin to its downstream metabolic effects are not completely understood. Epidemiological studies have demonstrated that excess lipid accumulation in non-adipose tissues, such as liver and skeletal muscle, promotes a lipotoxic state and results in insulin resistance, highlighting the importance of lipid accumulation in the pathogenesis of metabolic syndrome. In normal physiology, feeding triggers the release of insulin, which suppresses glucose production and activates lipogenesis in the liver; in obesity and type 2 diabetes, insulin fails to suppress glucose production and lipogenesis is paradoxically enhanced. At the molecular level, increased lipogenesis observed in the insulin-resistant state is due, at least in part, to dysregulation of the master transcriptional regulator of lipogenesis, namely sterol regulatory element-binding protein (SREBP)-1c. The SREBP family, originally identified as basic helix-loop-helix (bHLH) leucine zipper transcription factors by Brown and Goldstein, is involved in the regulation of the entire complement of genes necessary for the synthesis of fatty acids (FAs), triglycerides (TGs), and cholesterol. The SREBP family consists of three isoforms: SREBP-1a, SREBP-1c, and SREBP-2. The biosynthesis of FAs and TGs is controlled by SREBP-1c, the upregulation of genes involved in cholesterol metabolism is preferentially governed by SREBP-2, and SREBP-1a activates both FA and cholesterol biosynthetic pathways. Expression of SREBP-2 is induced under conditions of sterol depletion, whereas SREBP-1c expression is under the control of insulin, glucose, and FAs. Insulin activates SREBP-1c through at least two mechanisms: (i) it increases SREBP-1c transcription; (ii) it increases the proteolytic cleavage of SREBP-1c from an inactive endoplasmic reticulum (ER) membrane-bound precursor to release the N-terminal domain, which is capable of translocating to the nucleus to activate transcription (Figure 1). In hepatocytes, insulin signaling through phosphatidylinositol 3-kinase (PI3K) and AKT results in activation of SREBP-1c expression and accumulation of nuclear SREBP-1c protein; the major downstream effector of PI3K/AKT is mammalian target of rapamycin complex 1 (mTORC1). This conclusion is based on studies showing that insulin-stimulated SREBP activation and lipogenesis are both blocked by the mTORC1 inhibitor rapamycin. Activation of PI3K/AKT leads to direct phosphorylation of tuberous sclerosis complex (TSC) 1/2 and proline-rich Akt substrate 40 kDa (PRAS40), resulting in mTORC1 activation. In TSC1/2-null mouse embryonic fibroblasts (MEFs), mTORC1 is constitutively active and independent of upstream signals. SREBP-1 is activated in TSC1/2 null MEFs and SREBP-1 activation is inhibited following rapamycin treatment, indicating that mTORC1 activation is sufficient to stimulate SREBP-1 activity. Inhibition of S6 kinase, a downstream target of mTORC1, inhibits SREBP-1 processing in TSC1/2-null MEFs, but fails to block insulin-induced SREBP-1c activation in primary rat hepatocytes, suggesting the existence of S6 kinase-independent SREBP-1c regulation by mTORC1. A recent study revealed an additional important component of the AKT regulatory pathway, lipin-1. Lipin-1, a phosphatidic acid phosphatase (PAP) and transcriptional coactivator, is a direct substrate of mTORC1 and regulator of nuclear SREBP activity. Lipin-1 phosphorylation by mTORC1 blocks its nuclear localization and activates both SREBP-1 and SREBP-2. Conversely, expression of a non-phosphorylated form of lipin-1 results in Glucose ER