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Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells.
J Hepatol. 2013 Nov; 59(5):1045-53.JH

Abstract

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS-Esther Koplowitz Center, Barcelona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23831119

Citation

Morán-Salvador, Eva, et al. "Cell-specific PPARγ Deficiency Establishes Anti-inflammatory and Anti-fibrogenic Properties for This Nuclear Receptor in Non-parenchymal Liver Cells." Journal of Hepatology, vol. 59, no. 5, 2013, pp. 1045-53.
Morán-Salvador E, Titos E, Rius B, et al. Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. J Hepatol. 2013;59(5):1045-53.
Morán-Salvador, E., Titos, E., Rius, B., González-Périz, A., García-Alonso, V., López-Vicario, C., Miquel, R., Barak, Y., Arroyo, V., & Clària, J. (2013). Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. Journal of Hepatology, 59(5), 1045-53. https://doi.org/10.1016/j.jhep.2013.06.023
Morán-Salvador E, et al. Cell-specific PPARγ Deficiency Establishes Anti-inflammatory and Anti-fibrogenic Properties for This Nuclear Receptor in Non-parenchymal Liver Cells. J Hepatol. 2013;59(5):1045-53. PubMed PMID: 23831119.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. AU - Morán-Salvador,Eva, AU - Titos,Esther, AU - Rius,Bibiana, AU - González-Périz,Ana, AU - García-Alonso,Verónica, AU - López-Vicario,Cristina, AU - Miquel,Rosa, AU - Barak,Yaacov, AU - Arroyo,Vicente, AU - Clària,Joan, Y1 - 2013/07/02/ PY - 2013/03/06/received PY - 2013/06/19/revised PY - 2013/06/24/accepted PY - 2013/7/9/entrez PY - 2013/7/9/pubmed PY - 2014/10/1/medline KW - 4-HNE KW - 4-hydroxynonenal KW - ALT KW - AST KW - Alb-Cre KW - CCl(4) KW - Fibrosis KW - HSCs KW - Hepatic stellate cells KW - Hepatocytes KW - IL KW - Inflammation KW - Kupffer cells KW - LDH KW - LPS KW - LysM-Cre KW - NAFLD KW - NF-κB KW - PCLS KW - PPARγ KW - TNF-α KW - TZD KW - aP2-Cre KW - adipocyte fatty acid-binding protein 4-Cre (HSC-specific PPARγ deficient mice) KW - alanine aminotransferase KW - albumin-Cre (hepatocyte-specific PPARγ deficient mice) KW - aspartate aminotransferase KW - carbon tetrachloride KW - hepatic stellate cells KW - interleukin KW - lactate dehydrogenase KW - lipopolysaccharide KW - lysozyme M-Cre (macrophage-specific PPARγ deficient mice) KW - non-alcoholic fatty liver disease KW - nuclear factor-kB KW - peroxisome proliferator-activated receptor γ KW - precision-cut liver slices KW - thiazolidinediones KW - tumor necrosis factor α SP - 1045 EP - 53 JF - Journal of hepatology JO - J. Hepatol. VL - 59 IS - 5 N2 - 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. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/23831119/Cell_specific_PPARγ_deficiency_establishes_anti_inflammatory_and_anti_fibrogenic_properties_for_this_nuclear_receptor_in_non_parenchymal_liver_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(13)00440-6 DB - PRIME DP - Unbound Medicine ER -