Constitutive Role for IRE1α-XBP1 Signaling Pathway in the Insulin-Mediated Hepatic Lipogenic Program

Abstract

The role of the IRE1α-X-box-binding protein 1 (XBP1) pathway in the insulin-mediated hepatic lipogenic program and associated mechanisms were investigated in this study. We observed that phosphorylation of IRE1α (an upstream activator of XBP1) and splicing (activation) of XBP1 were elevated in the liver of the C57BL/6 mice with insulin resistance/hyperinsulinemia induced by high-fat diet. Treatment of nonobese diabetic mice with insulin activated hepatic XBP1. In cultured primary mouse hepatocytes, prolonged exposure to insulin induced IRE1α phosphorylation and XBP1 splicing significantly in the presence of insulin resistance. Overexpression of the activated XBP1 elevated the promoter activities of the sterol regulatory element-binding protein (SREBP)-1c and fatty acid synthase (FAS) genes. Knockdown of either the IRE1α or XBP1 gene by small interfering RNA prevented the insulin-stimulated promoter activities of both SREBP-1 and FAS genes. In investigating the associated mechanisms, we found a direct interaction between XBP1 and SREBP-1 promoter detected by the chromatin immunoprecipitation assays. Furthermore, the XBP1-mediated stimulation of the FAS promoter was eliminated by knocking down the SREBP-1c gene (Srebf1). Finally, we observed that insulin activation of the IRE1α-XBP1 pathway was prevented by inhibition of mammalian target of rapamycin-dependent protein synthesis. In conclusion, our results show that the IRE1α-XBP1-mediated unfolded protein response pathway is an integrated part of the insulin-induced hepatic lipogenic program and functions at an increased basal level in the presence of insulin resistance and hyperinsulinemia. Besides, the insulin-mediated protein synthesis is tightly connected with the insulin-mediated lipogenic program.

Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

“…Indeed, fat accumulation in the liver of CypD-KO mice seems to be related to both a reduction in lipid oxidation (based on reduction in Cpt1 expression) and an induction of de novo lipogenesis (based on induction of lipogenic genes), whereas esterification of lipid (based on the absence of change in circulating NEFA levels) and export of lipids (based on induction of ApoB and Mttp genes) from liver should not be altered. The induction of de novo lipogenesis is in agreement with the activation of both PERK and IRE1 branches of the unfolded protein response in the liver of CypD-KO mice, as both pathways were shown to activate the lipogenic transcription factor SREBP-1c [25][26][27]. Particularly, accumulation of DAG likely contributes to PKCε activation in the liver of CypD-KO mice.…”

Targeting endoplasmic reticulum stress in insulin resistance

“…Strikingly, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a key regulator of SREBP-1 expression, activates ER stress to promote hepatic IR and lipid accumulation [23]. Additional mechanisms involved in SREBP-1c activation by ER stress include rapid degradation of its upstream inhibitor insulin-induced gene 1 (Insig1) [26] and direct transcriptional activation of the SREBP-1c gene by the IRE-1a-XBP1 pathway [27]. Of note, XBP1 is also capable of enhancing the degradation of lipogenic mRNAs through a SREBP-1c-independent mechanism, in a process known as regulated IRE-1-dependent decay (RIDD, Box 1) [28].…”

Contribution of mitochondria and endoplasmic reticulum dysfunction in insulin resistance: Distinct or interrelated roles?

“…• transcription factors that modulate the expression of key hepatic enzymes involved in both gluconeogenesis and lipogenesis, leading to abnormal activation of these pathways in IR states [46][47][48] and; • cleavage of sterol regulatory element-binding protein-1c (SREBP1c) [49], thus promoting fat accumulation in hepatocytes and further exacerbating hepatic IR.…”