Myeloid Nrf2 deficiency aggravates non-alcoholic steatohepatitis progression by regulating YAP-mediated NLRP3 inflammasome signaling

Nuclear-erythroid-2-related factor 2 (Nrf2) is involved in the pathogenesis of different liver diseases. Herein, we first demonstrated that Nrf2 expression was diminished in nonalcoholic steatohepatitis (NASH) liver macrophages. In myeloid Nrf2-deficiency mice, aggravated liver steatosis and inflammation in high-fat-diet (HFD)-fed mice were observed compared with the chow-diet group. Moreover, the increasing inflammatory cytokines influenced the lipid metabolism in hepatocytes in vivo and in vitro. Further study showed Nrf2 regulated reactive-oxygen-species-mediated Hippo-yes-associated protein (YAP) signaling, which in turn modulated the NLRP3 inflammasome activation. Administration of YAP activator also significantly ablated the lipid accumulation and inhibited the NLRP3 activation in the Nrf2 deletion condition both in vitro and vivo. Overexpression Nrf2 in liver macrophages effectively alleviated steatohepatitis in wild-type mice fed with an HFD . Our data support that by modulating YAP-mediated NLRP3 inflammasome activity, macrophage Nrf2 slows down NASH progression. [Display omitted] •Kupffer cells Nrf2 was downregulated in both human and mouse NASH livers•Myeloid Nrf2 deficiency aggravates liver steatosis and inflammation in HFD-induced NASH•Nrf2 controls the NLRP3 activation in a ROS-mediated Hippo-YAP signaling manner Immunology; Physiology; Endocrine System Physiology; Human Metabolism