Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B
J. Hepatol. 2018 Jun;
The obesity epidemic is accompanied by a worldwide burden of non-alcoholic fatty liver disease (NAFLD) that manifests from simple steatosis to non-alcoholic steatohepatitis (NASH), possibly evolving into hepatocellular carcinoma (HCC). Although much attention has been focused on NAFLD, its pathogenesis remains largely obscure. The hallmark of NAFLD is the hepatic accumulation of lipids subsequently leading to cellular stress and hepatic injury, which eventually results 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 signaling pathway known as the Unfolded Protein Response (UPR) is triggered initially to restore ER proteostasis. The UPR can be accountable for inflammation, inflammasome activation and, in the case of non-resolvable ER stress, for the death of hepatocytes. Experimental data suggest that the UPR influences hepatic tumor 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.