Insulin Enhances the Biogenesis of Nuclear Sterol Regulatory Element-binding Protein (SREBP)-1c by Posttranscriptional Down-regulation of Insig-2A and Its Dissociation from SREBP Cleavage-activating Protein (SCAP)·SREBP-1c Complex

Abstract

The regulation of lipid homeostasis by insulin is mediated in part by the enhanced transcription of the gene encoding sterol regulatory element-binding protein-1c (SREBP-1c). The nascent SREBP-1c is embedded in the endoplasmic reticulum (ER) and must be transported to the Golgi where two sequential cleavages generate its NH(2)-terminal fragment, nSREBP-1c. We have shown recently that in primary cultures of rat hepatocytes, insulin rapidly and selectively stimulates proteolytic processing of the nascent SREBP-1c by enhancing the affinity of the SREBP cleavage-activating protein (SCAP).SREBP-1c complex for coatomer protein complex II (COPII) vesicles. The SCAP.SREBP complex is retained in the ER by Insig proteins. We report here that insulin persistently stimulates controlled proteolysis of the nascent SREBP-1c by selectively reducing the level of Insig-2a protein via accelerated degradation of its cognate mRNA. Insulin enhanced the rate of turnover of Insig-2a mRNA via its 3'-untranslated region. Insulin-induced depletion of Insig-2a promotes association of the SCAP.SREBP-1c complex with COPII vesicles and subsequent migration to the Golgi where site-1 and site-2 proteases process the nascent SREBP-1c. Consistent with this mechanism, experimental knockdown of Insig-2a expression with small interfering RNA mimicked insulin-induced proteolysis of the nascent SREBP-1c, whereas exogenous expression of Insig-2a in hepatocytes led to reduced intramembrane proteolysis of the newly synthesized SREBP-1c. The action of insulin on the processing of the nascent SREBP-1c via Insig-2a was highly selective, as proteolysis of the newly synthesized SREBP-2 remained unchanged under identical conditions. On the basis of these data, we propose that the stimulation of SREBP-1c processing by insulin is mediated by a selective depletion of Insig-2a protein by promoting decay of its cognate mRNA. Thus, insulin-induced reduction in Insig-2a protein leads to an enhanced export of the SCAP.SREBP-1c complex from ER to the Golgi.

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

“…In addition to LXR, in response to insulin, SREBP-1c production is also mediated by the cleaved nuclear form of SREBP-1c itself, which mediates transactivation on the SREBP-1c promoter [33]. A study by Yellaturu et al clearly shows that insulin enhances SREBP-1c production by inducing cleavage of precursor SREBP-1c to its nuclear form [34]. In the resting state, the SCAP-SREBP1c complex is localised to the ER by INSIG2.…”

“…In the resting state, the SCAP-SREBP1c complex is localised to the ER by INSIG2. However, in response to stimuli, INSIG2 dissociates from the SCAP-SREBP-1c complex, thereby facilitating transport of the complex to the Golgi where immature SREBP-1c is cleaved to generate the active form of SREBP-1c [34]. Insulin enhances the rate of turnover of Insig2 mRNA, and insulin-induced depletion of Insig2 promotes proteolysis of SREBP-1c, resulting in active SREBP-1c.…”

“…In mammals, fasting decreases and re-feeding increases hepatic lipid synthesis [29]. Insulin is a potent inducer of hepatic lipogenesis during feeding [7,29], and this may be transcriptionally mediated by SREBP-1c [28,34,35]. In the The data represent the mean ± SE of three independent measurements (n06 in each group).…”

Lysophosphatidic Acid Activates Lipogenic Pathways and de Novo Lipid Synthesis in Ovarian Cancer Cells

“…An increase in SCAP or a decrease in INSIG proteins could lead to activation of SREBP. Because androgens and insulin have been shown to regulate expression or stability of SCAP or INSIG (65,66), it will be of interest to determine whether LPA modulates these proteins or their ratios to activate SREBP. This possibility is consistent with the observation that SREBP cleavage occurs hours after exposure of ovarian cancer cells to LPA.…”

Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

“…Here, SREBPs activate transcription by binding to sequences in the promoters of target genes. Insulinmediated stimulation of SREBP1-c processing and SREBP1-c mRNA induction requires PI 3-kinase/Akt/mTORC1 signaling, and either rapamycin or PI 3-kinase inhibitors block its activation (47,49,59,64,68,69,78,79).…”