Background & aims: PPARγ plays an essential role in the transcriptional regulation of genes involved in lipid and glucose metabolism, insulin sensitivity, and inflammation. We recently demonstrated that PPARγ plays a causative role in hepatocyte lipid deposition, contributing to the pathogenesis of hepatic steatosis. In this study, we investigated the role of PPARγ in the inflammatory and fibrogenic response of the liver.
Methods: Heterozygous floxed/null Cre/LoxP mice with targeted deletion of PPARγ in either hepatocytes (Alb-Cre), macrophages (LysM-Cre) or hepatic stellate cells (HSCs) (aP2-Cre) were submitted to carbon tetrachloride (CCl4) liver injury. Further analyses were performed in precision-cut liver slices (PCLS) and primary cultures of hepatocytes, macrophages, and HSCs.
Results: LysM-Cre mice displayed an exacerbated response to chronic CCl4 injury and showed higher necroinflammatory injury, lipid peroxidation, inflammatory infiltrate, cleaved-caspase-3 and caspase 3/7 activity, and COX-2, TNF-α, CXCL2, and IL-1β expression than Alb-Cre and control mice. The deleterious effects of PPARγ disruption in liver macrophages were confirmed in an acute model of CCl4 injury as well as in PCLS incubated with LPS. Moreover, LysM-Cre mice showed an aggravated fibrogenic response to CCl4, as revealed by more prominent Sirius Red and Masson's trichrome staining, elevated hydroxyproline content and induced α-SMA and TIMP-1 expression. Importantly, aP2-Cre mice with specific disruption of PPARγ in HSCs, as confirmed by immunocytochemical analysis of individual liver cells, also showed exacerbated liver damage and fibrogenic response to CCl4.
Conclusions: These data unveil anti-inflammatory and anti-fibrogenic roles for PPARγ in non-parenchymal liver cells.
Keywords: 4-HNE; 4-hydroxynonenal; ALT; AST; Alb-Cre; CCl(4); Fibrosis; HSCs; Hepatic stellate cells; Hepatocytes; IL; Inflammation; Kupffer cells; LDH; LPS; LysM-Cre; NAFLD; NF-κB; PCLS; PPARγ; TNF-α; TZD; aP2-Cre; adipocyte fatty acid-binding protein 4-Cre (HSC-specific PPARγ deficient mice); alanine aminotransferase; albumin-Cre (hepatocyte-specific PPARγ deficient mice); aspartate aminotransferase; carbon tetrachloride; hepatic stellate cells; interleukin; lactate dehydrogenase; lipopolysaccharide; lysozyme M-Cre (macrophage-specific PPARγ deficient mice); non-alcoholic fatty liver disease; nuclear factor-kB; peroxisome proliferator-activated receptor γ; precision-cut liver slices; thiazolidinediones; tumor necrosis factor α.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.