Regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease

BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).Various studies have shown that PPAR-γexerts potent anti-inflammatory and immunomodulatory properties.However,little is known about the regulation of PPAR-γactivity in modulating cell crosstalk in NAFLD.AIM To investigate whether the regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation.METHODS Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocytespecific PPAR-γknockout mice and incubated with free fatty acids(FFAs).Macrophages were incubated with conditioned medium(CM)from lipid-laden hepatocytes with or without a PPAR-γagonist.Wild-type C57BL/6J mice were fed a high-fat(HF)diet and administered rosiglitazone.RESULTS Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs.CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway.A PPAR-γagonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization.Hepatocyte-specific PPAR-γdeficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes,which further promoted M1 macrophage polarization.Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.CONCLUSION Upregulation of PPAR-γactivity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1βpathway.