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Hyperlipidemia is reemerging as an important cardiovascular disease risk factor and other metabolic disorders, such as obesity, insulin resistance and type-2 diabetes. Hepatic de novo lipogenesis is controlled by a family of the b-zip transcription factors, the sterol regulatory element-binding proteins (SREBPs), which targets downstream genes involved in free fatty acids, triglycerides and cholesterol synthesis. Regulation of SREBPs signaling is controlled by a cluster of the ER membrane-bound proteins, the insulin induced gene-1(Insig-1) and gene-2 (Insig-2) and the SCAP protein. The cAMP responsive element binding protein H (CREBH) is a recently identified member of this family. CREBH is selectively and highly expressed in the liver and small intestine which is actively involved in lipid and glucose metabolism. However, its underlying molecular mechanisms are not fully understood. Here we demonstrated CREBH inhibits hepatic lipid de novo synthesis through modulating the expression of insulin induced gene-2 (Insig-2) isoform-a, a liver specific isoform of Insig-2, which is involved in the activation of sterol regulatory element-binding proteins (SREBPs). Metabolic cues, such as fasting, glucagon and cAMP agonist, activated CREBH which in turn inhibited SREBP-1c and SREBP-2 activation via upregulate the abundance of Insig-2a in hepatocytes. Depletion or suppression of CREBH expression by refeeding inhibited Insig-2a expression, which in turn hyperactivated SREBP-1c and -2, leading to the activation of hepatic de novo lipid synthesis, accumulation of lipids in hepatocytes and systemic hyperlipidemia. We further demonstrated that depletion of CREBH reduced both mRNA and protein expression of apolipoprotein B (apoB). In vitro, transient expression of CREBH cDNAs in McA cells induced significant increase of apoB mRNA and protein expression, which indicated the positive regulatory impact of CREBH on apoB biosynthesis. This study establishes the CREBH-Insig-2a as a novel metabolic pathway that regulates hepatic de novo lipogenesis. This novel finding provides new mechanistic insight into the pathogenesis of hyperlipidemia in metabolic diseases.
Advisor: Qiaozhu Su