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

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.