Nrf2 repression by endoplasmic reticulum stress facilitates nonalcoholic steatosis progression to steatohepatitis

Nonalcoholic steatohepatitis (NASH) is characterized by progression of steatosis to hepatitis with ballooning degeneration and inflammation. Of note, only a portion of patients with steatosis develop NASH. However, the hit that determines NASH transition remains unclear. This study investigated the impact of endoplasmic reticulum (ER) stress on erythroid 2‐related factor 2 (Nrf2) and their roles in NASH development. In patients with NASH, levels of hepatic XBP‐1s and Grp78 were elevated compared with healthy individuals or steatosis patients. Either diet‐induced obese mice or ob / ob mice exhibited a positive correlation between ER stress marker levels and liver injury. Consistently, treatment of mice with ER stress inducer triggered hepatocyte injury, which was preceded by Nrf2 repression. A deficiency of Nrf2 enhanced ER stress, whereas its activation had the opposing effect. Nrf2 promoted the expression of CPT1, PPARa/d and PGC1a, enhancing oxygen consumption and ATP generation. ER stress diminished the ability of Nrf2 to increase CPT1, PPARa/d and PGC1a levels. In the samples of patients with NASH or of mice fed a HFD, Nrf2 was persistently repressed. Experiments using over‐expression construct and siRNA revealed that enforced expression of Nrf2 prevented the progression of steatosis to steatohepatitis against ER stress. These results show that ER stress‐dependent repression of Nrf2 and the consequent decrease of antioxidant capacity may promote the transition of steatosis to steatohepatitis.