Abstract 434: Insig-2a Links CREBH Signaling to Hepatic Lipogenesis and Systemic Hyperlipidemia
The sterol regulatory element binding proteins (SREBPs) are master transcription factors that regulate hepatic de novo lipogenesis. Perturbation of SREBPs functionality is closely related to the onset of hyperlipidemia. The current investigation sought to advance our understanding on the activation of SREBP-1c via the interplay between the cAMP responsive element binding protein H (CREBH) and the liver specific insulin-induced gene 2a isoform (Insig-2a). Genetic depletion of CREBH specifically down regulated expression of both Insign-2a mRNA and protein levels which resulted in the hyperactivation of SREBP-1c and the subsequent hypertriglyceridemia. Challenging wild type (WT) mice with a high fat diet
(HFD) specifically stimulated expression of Insig-2a mRNA and protein in the WT mice. In contrast, HFD failed to enhance expressions of Insig-2a mRNA and protein in CREBH-null mice. No alterations were detected on the mRNA transcription of another Insig-2 isoform, Insig-2b, in the livers of WT mice and CREBH-null mice under both chow and HFD conditions. Decrease of Insig-2a caused activation of hepatic de novo lipogenesis, mainly via SREBP-1c activation, which contributed to the development of sever systemic hypertriglyceridemia and hepatic steatosis in CREBH-null mice. Consistent with the in vivo observation, forced expression of CREBH cDNA in a rat hepatoma cell line, McA cells, specifically increased expressions of both Insig-2a mRNA and protein which in turn inhibited activation of SCREBP-1c. Analyzing the gene promoter of Insig-2a, we identified a CREB binding site at the promoter of the Insig-2a and a ChIP assay further confirmed the physical association between CREBH and the Insig-2a promoter. These data identify Insig-2a as a target gene of CREBH. Modulation of Insig-2a expression by CREBH is essentially involved in regulating hepatic triglyceride metabolism. Given the role of CREBH in hepatic acute phage response signaling, this finding further reveals the cross-talk between inflammatory and insulin signal pathways in maintaining systemic lipid homeostasis and may provide rationale for pharmaceutical design to specifically target CREBH and insig-2a in the prevention and treatment of hypertriglyceridemia.
- © 2013 by American Heart Association, Inc.