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 in vivo 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 in vivo 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 in vitro 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.
Highlights
Non-alcoholic fatty liver diseases (NAFLD) contains a broad histopathological spectrum ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), which can result in hepatic cirrhosis and even liver cancer [1, 2]
The phosphorylation levels of AMPK, JNK, and ErK1/2 were markedly reduced in adiponectin deficiency mice, while there was no remarkable alteration in the protein levels of total AMPK, JNK, and ErK1/2 (Figures 2C–E). These results suggest that adiponectin deficiency promotes HFD-induced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation pathways (NFκB and reactive oxygen species (ROS)) and attenuates AMPK/JNK/ErK1/2 signaling pathways
Given that palmitic acid (PA) could induce NFκB phosphorylation and ROS production (Figures 6A–F) that act as the regulators of NLRP3 inflammasome activation [12], we further assessed the effects of adiponectin and Compound C on PA-mediated NFκB and ROS expression, It was found that adiponectin inhibited PA-mediated NFκB phosphorylation and ROS production in hepatocytes, and Compound C reversed the suppressive effects of adiponectin on PA-mediated NFκB expression and ROS production (Figure 6F). These findings reveal that adiponectin can suppress PA-mediated NLRP3 inflammasome activation in hepatocytes via AMPKJNK/extracellular signalregulated kinase1/2 (Erk1/2)-NFκB/ROS signaling pathways
Summary
Non-alcoholic fatty liver diseases (NAFLD) contains a broad histopathological spectrum ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), which can result in hepatic cirrhosis and even liver cancer [1, 2]. NASH is highly associated with obesity, insulin resistance, hypertension, and diabetes mellitus [3]. With the changes in human diet and lifestyle, the incidence rates of NAFLD and NASH are increased at an alarming rate, which has become the leading cause of chronic hepatic diseases [4, 5]. New insights into the molecular mechanism of NASH have been provided. Numerous studies have suggested the involvement of inflammasome activation in the pathogenesis of NASH [7,8,9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
