Adiponectin Inhibits NLRP3 Inflammasome Activation in Nonalcoholic Steatohepatitis via AMPK-JNK/ErK1/2-NFκB/ROS Signaling Pathways

Abstract

Adiponectin, an adipose-derived adipokine, possesses a hepatoprotective role in various liver disorders. It has been reported that hypoadiponectinemia can affect with the progression of non-alcoholic fatty liver diseases (NAFLD). Inflammasome activation has been recognized to play a major role during the progression of NAFLD. This research aimed to explore the effect of adiponectin on palmitate (PA)-mediated NLRP3 inflammasome activation and its potential molecular mechanisms. Male adiponectin-knockout (adiponectin-KO) mice and C57BL/6 (wild-type) mice were fed a high-fat-diet (HFD) for 12 weeks as an <i>in vivo</i> model of non-alcoholic steatohepatitis (NASH). Serum biochemical markers, liver histology and inflammasome-related gene and protein expression were determined. In addition, the hepatocytes isolated from wide type mice were exposed to PA in the absence or presence of adiponectin and/or AMPK inhibitor. The activation of NLRP3 inflammasome was assessed by mRNA and protein expression. Furthermore, ROS production and related signaling pathways were also evaluated. In the <i>in vivo</i> experiments, excessive hepatic steatosis with increased NLRP3 inflammasome and its complex expression were found in adiponectin-KO mice compared to wild-type mice. Moreover, the expression levels of NLRP3 inflammasome pathway molecules (NFκB and ROS) were upregulated, while the phosphorylation levels of AMPK, JNK, and Erk1/2 were downregulated in adiponectin-KO mice compared with wild-type mice. In the <i>in vitro</i> study, PA increased lipid droplet deposition, NF-kB signaling and ROS production. Additionally, PA significantly promoted NLRP3 inflammasome activation and complex gene and protein expression in hepatocytes. Adiponectin could abolish PA-mediated inflammasome activation and decrease ROS production, which was reversed by AMPK inhibitor (compound C). Furthermore, the results showed that the inhibitory effect of adiponectin on PA-mediated inflammasome activation was regulated by AMPK-JNK/ErK1/2-NFκB/ROS signaling pathway. Adiponectin inhibited PA-mediated NLRP3 inflammasome activation in hepatocytes. Adiponectin analogs or AMPK agonists could serve as a potential novel agent for preventing or delaying the progression of NASH and NAFLD.