stf-083010 and Insulin-Resistance

The global epidemic of obesity has been accompanied by a rising burden of non-alcoholic fatty liver disease (NAFLD), with manifestations ranging from simple steatosis to non-alcoholic steatohepatitis, potentially developing into hepatocellular carcinoma. Although much attention has focused on NAFLD, its pathogenesis remains largely obscure. The hallmark of NAFLD is the hepatic accumulation of lipids, which subsequently leads to cellular stress and hepatic injury, eventually resulting in chronic liver disease. Abnormal lipid accumulation often coincides with insulin resistance in steatotic livers and is associated with perturbed endoplasmic reticulum (ER) proteostasis in hepatocytes. In response to chronic ER stress, an adaptive signalling pathway known as the unfolded protein response is triggered to restore ER proteostasis. However, the unfolded protein response can cause inflammation, inflammasome activation and, in the case of non-resolvable ER stress, the death of hepatocytes. Experimental data suggest that the unfolded protein response influences hepatic tumour development, aggressiveness and response to treatment, offering novel therapeutic avenues. Herein, we provide an overview of the evidence linking ER stress to NAFLD and discuss possible points of intervention.

Topics: Activating Transcription Factor 6; Animals; Autophagy; Calcium; Endoplasmic Reticulum Stress; Genetic Therapy; Humans; Insulin Resistance; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Signal Transduction; Sulfonamides; Thiophenes; Unfolded Protein Response

Wnt/β-catenin signaling is involved in glucose and lipid metabolism, but the mechanism is not clear yet.. The objective is to study mechanisms of Wnt/β-catenin signaling on regulating hepatocytes metabolism.. Real-time qPCR, Western blot, and Oil-red O staining methods were used.. The Wnt/β-catenin signaling was activated in hepatocytes by CP21R7, and the level of phosphorylated IRS-1 (Ser307) and TRB3 were significantly increased, while the levels of phosphorylated IRS-1 (Tyr612) and phosphorylated Akt were decreased. Moreover, the expression of FGF21, FAS, SCD1, PPARγ and ADRP was significantly increased. The expression of ATF4, ATF5, eIF2α, GRP78, CHOP and phosphorylated level of PERK were also increased. The expression of FGF21 and TRB3 was significantly down-regulated, and the lipid droplets were notably reduced after the ER stress was inhibited by TUDCA. The expression of FGF21 was significantly decreased when the IRE1 pathway of the UPR was inhibited by STF-083010.. Activation of Wnt/β-catenin signaling pathway could cause insulin resistance and lipogenesis in hepatocytes via regulation of the IRE1 pathway of the ER stress and UPR, providing new targets for the treatment of metabolic disorders.

Topics: Activating Transcription Factors; beta Catenin; Down-Regulation; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Endoribonucleases; Eukaryotic Initiation Factor-2; Heat-Shock Proteins; Hep G2 Cells; Hepatocytes; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance; Lipogenesis; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Sulfonamides; Thiophenes; Transcription Factor CHOP; Wnt Proteins; Wnt Signaling Pathway