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  • br Introduction Hepatocyte injury initiates

    2021-09-14


    Introduction Hepatocyte injury initiates and facilitates inflammation in the course of liver disease progression. Thus, understanding the regulatory basis for sensing and responding to damage-associated inflammatory processes in the liver’s parenchymal cells is a primary issue in liver pathophysiology. The inflammasome is a multiprotein complex that senses cellular danger signals, and its activation leads to interleukin (IL)-1β production (Guo et al., 2015). Emerging evidence suggests that the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in hepatocytes plays a role in the pathogenesis of liver diseases (Szabo and Csak, 2012, Szabo and Petrasek, 2015). In particular, saturated fatty Spermine NONOate activates the NLRP3 inflammasome and sensitizes hepatocytes to endotoxin response, leading to non-alcoholic steatohepatitis (NASH) (Csak et al., 2011). Uric acid also induces fat accumulation in the liver and insulin resistance through the NLRP3 inflammasome (Wan et al., 2016). Thus, NLRP3 has an impact on hepatocyte death, inflammation, and potentially on the progression of liver fibrosis, as shown in an animal study (Wree et al., 2014). Nevertheless, the endogenous molecules and pathways that regulate these NLRP3-mediated events are largely unknown. Multiple disturbances that cause the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) trigger the ER stress response (i.e., the unfolded protein response [UPR]; Hetz, 2012). Chronic or irremediable ER stress then induces cellular dysfunction and eventually leads to cell death, which is closely associated with hepatic inflammation (Dara et al., 2011, Malhi and Kaufman, 2011). NLRP3 is a member of the inflammasome family that is activated by diverse pathological stimuli, including extracellular ATP, cholesterol crystals, and reactive oxygen species, as well as microbial pathogens (Szabo and Csak, 2012, Szabo and Petrasek, 2015), suggestive of its critical role in sterile inflammation. It has also been proposed that ER stress is linked to the NLRP3 inflammasome in pancreatic beta cells (Lerner et al., 2012, Oslowski et al., 2012). ER stress also induces inflammasome activation in hepatocytes, potentially causing liver injury (Lebeaupin et al., 2015). However, the hepatic regulator that acts to ameliorate ER stress and the inflammasome remains unknown. Farnesoid X receptor (FXR) (NR1H4) serves as a ligand-mediated transcription factor that controls the expression of various genes involved in bile acid, lipid, and glucose metabolism (Calkin and Tontonoz, 2012, Teodoro et al., 2011). FXR plays a role in the maintenance of liver homeostasis and is also important for mitochondrial function and cellular integrity (Lee et al., 2012, Wang et al., 2008). The ligand-mediated activation of FXR in the liver has beneficial effects against metabolic disorders. Indeed, FXR ligands have been tested in clinical trials for the treatment of non-alcoholic fatty liver disease (NAFLD), diabetes, and cholestasis (Adorini et al., 2012, Beuers et al., 2015, Carr and Reid, 2015). However, the anti-inflammatory effect exerted by FXR in hepatocytes, in particular, in the context of liver protection against ER stress-mediated injury needs to be established. In view of the lack of an understanding about NLRP3 regulators and of the potential anti-inflammatory action of FXR in hepatocytes, this study investigated the inhibitory role of FXR in NLRP3 inflammasome activation in response to ER stress. First, we used bioinformatic approaches and analyzed human liver samples to investigate the action of FXR on the target of interest and performed loss- or gain-of-function experiments in animal and cell models. Our results demonstrate that FXR levels in the liver inversely correlate with those of inflammasome gene expression in patients with hepatitis B virus (HBV)-associated liver failure or with NAFLD and that ligand-mediated activation of FXR prevents ER stress from activating the NLRP3 inflammasome in hepatocytes. In addition, we found that FXR inhibits the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-CCAAT-enhancer-binding protein homologous protein (CHOP) pathway, inhibiting the priming and activation steps of the NLRP3 inflammasome. We further propose, based on our findings from in vivo and in vitro ER stress models, that miR-186 and its potential target, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), mediates the inhibition of ER stress by FXR.