Cell-specific PPAR gamma deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells

作者：Moran Salvador Eva; Titos Esther; Rius Bibiana; Gonzalez Periz Ana; Garcia Alonso Veronica; Lopez Vicario Cristina; Miquel Rosa; Barak Yaacov; Arroyo Vicente; Claria Joan^*

来源：Journal of Hepatology, 2013, 59(5): 1045-1053.

• PPAR gamma
• Kupffer cells
• Hepatic stellate cells
• Hepatocytes
• Inflammation
• Fibrosis

Background & Aims: PPAR gamma plays an essential role in the transcriptional regulation of genes involved in lipid and glucose metabolism, insulin sensitivity, and inflammation. We recently demonstrated that PPAR gamma plays a causative role in hepatocyte lipid deposition, contributing to the pathogenesis of hepatic steatosis. In this study, we investigated the role of PPAR gamma in the inflammatory and fibrogenic response of the liver.
Methods: Heterozygous floxed/null Cre/LoxP mice with targeted deletion of PPAR gamma 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-alpha, CXCL2, and IL-1 beta expression than Alb-Cre and control mice. The deleterious effects of PPAR gamma 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 alpha-SMA and TIMP-1 expression. Importantly, aP2-Cre mice with specific disruption of PPAR gamma 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 antifibrogenic roles for PPAR gamma in non-parenchymal liver cells.

• 出版日期2013-11