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

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• 作者：Eva Mor¨¢n-Salvador ; Esther Titos ; Bibiana Rius ; Ana Gonz¨¢lez-P¨¦riz ; Ver¨®nica Garc¨ªa-Alonso ; Cristina L¨®pez-Vicario ; Rosa Miquel ; Yaacov Barak ; Vicente Arroyo ; Joan Cl¨¤ria
• 关键词：PPAR¦Ã ; peroxisome proliferator-activated receptor ¦Ã ; TZD ; thiazolidinediones ; TNF-¦Á ; tumor necrosis factor ¦Á ; IL ; interleukin ; HSCs ; hepatic stellate cells ; NAFLD ; non-alcoholic fatty liver disease ; CCl4 ; carbon tetrachloride ; LPS ; lipopolysaccharide
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：59
• 期：5
• 页码：1045-1053
• 全文大小：2087 K

文摘

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Background & Aims

PPAR¦Ã 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¦Ã plays a causative role in hepatocyte lipid deposition, contributing to the pathogenesis of hepatic steatosis. In this study, we investigated the role of PPAR¦Ã in the inflammatory and fibrogenic response of the liver.

Methods

Heterozygous floxed/null Cre/LoxP mice with targeted deletion of PPAR¦Ã 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-¦Á, CXCL2, and IL-1¦Â expression than Alb-Cre and control mice. The deleterious effects of PPAR¦Ã 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 ¦Á-SMA and TIMP-1 expression. Importantly, aP2-Cre mice with specific disruption of PPAR¦Ã 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 PPAR¦Ã in non-parenchymal liver cells.