The effect of peroxisome proliferator-activated receptor-delta activator on fatty acid-induced inflammasome in human liver carcinoma cell line

Abstract

Background: Non-alcoholic steatohepatitis (NASH) is progressive form of nonalcoholic fatty liver disease and can lead to cirrhosis and even hepatocellular carcinoma (HCC). The inflammasome, a multiprotein complex formed by nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family members, has been recently shown to be activated in NASH. This study was designed to evaluate the inflammasome activation induced by palmitic acid (PA) and the effects of the peroxisome-proliferator activated receptor (PPAR)-δ agonist GW501516 in this condition.

Methods: Human HCC cell line(HepG2) was used in this study. PA (0.2 mM) and lipopolysaccharide (LPS) were used to induce inflammation. The cells were treated with PA (0.2 mM) and/or lipopolysaccharide (LPS) for 16 hours, along with PPAR-δ agonist (GW501516, 1 and 10μM). We measured the mRNA expression levels of inflammsome-related molecules using real time PCR analysis. Protein levels of inflammatory cytokines were determined by western blotting.

Results: In the group treated with PA plus LPS, there was a significantly increase in several inflammasome gene expression (including NLRP3, NLRP6, NLRP10, caspase-1) versus the control, PA or LPS-treatment group (P < 0.05). NLRP1 and NLRC4 mRNA expression levels were not affected by such stimulation. Inflammasome activation was indicated by higher mature IL-1βand caspase-1 protein levels in the PA plus LPS treatment group but not in the control group. All of the above effects of PA and LPS were attenuated by the PPAR-δ agonist GW 501516 in a dose dependent manner.

Conclusions: These results demonstrate that PPAR-δ agonist attenuates PA-induced inflammation through suppressing several inflammasome activation, caspase-1 activation and IL-1β cleavage. PPAR-δ agonist may serve as a potential therapeutic agent for NASH.