Progression of steatosis (NAFLD) to steatohepatitis and fibrosis (NASH) is associated with development of ER stress and activation of the unfolded protein response (UPR) to control hepatic protein and lipid homeostasis. Under physiological conditions, UPR is inactive (due to inhibitory binding of GRP78/BiP to IRE1, PERK, and ATF6) to maintain normal proteostasis in healthy hepatocytes. Upon GRP78 dissociation, all 3 arms of the UPR are activated. In response to chronic injury, all arms of the UPR contribute to NASH and, to different extents, support de novo lipogenesis.