Obeticholic acid improves hepatic steatosis and inflammation by inhibiting NLRP3 inflammasome activation.

Several pre-clinical and clinical researches have proved that obeticholic acid (OCA)has a potential therapeutic effect on non-alcoholic steatohepatitis (NASH). Our aim was to investigate whether the therapeutic effect of OCA on NASH was attributed to its inhibition effect on cytosolic sensor NLR family pyrin domain containing 3 (NLRP3) inflammasome activation.We used mice model of methionine-choline-deficient (MCD) diet induced NASH. At different fibrosis stages, the expressions of NLRP3, caspase-1 and IL-1β were analyzed by means of immunohistochemistry and western blot respectively. After daily gavage of 0.4 mg of OCA or vehicle for 24 days, we evaluated the direct effect of OCA on NLRP3 inflammasome activation by analyzing the expressions of NLRP3 and IL-1β. Additionally, liver function and liver histology of mice were assessed. The expressions of NLRP3 and IL-1β above and the expressions of fibrosis-related genes were analyzed by quantitative real-time polymerase chain reaction (PCR).NLRP3 inflammasome activation could be observed in liver fibrosis, and we found that the expressions of NLRP3, caspase-1 and IL-1β gradually increased to peak at stage 2-3 but decreased significantly at stage 4 of liver fibrosis in MCD mice model. We also found that short-term OCA treatment could significantly down-regulate the expressions of NLRP3 and IL-1β and therefore improved NASH-associated steatosis and inflammation.NLRP3 inflammasome could be activated and might have an essential role in NASH progression, and short-term OCA treatment could have a potential therapeutic effect on NASH-associated steatosis and inflammation by inhibiting NLRP3 inflammasome activation.