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Garcia-Alonso V.,Hospital Clinic Esther Koplowitz Center | Lopez-Vicario C.,Hospital Clinic Esther Koplowitz Center | Titos E.,Hospital Clinic Esther Koplowitz Center | Titos E.,CIBER ISCIII | And 11 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Microsomal prostaglandin E (PGE) synthase-1 (mPGES-1) is an inducible enzyme with unknown properties in adipose homeostasis. Results: mPGES-1 is necessary for pre-adipocyte differentiation into beige/brite adipocytes through functional interaction with peroxisome proliferator-activated receptor γ (PPARγ). Conclusion: A coordinate interaction between mPGES-1 and PPARγ is required for white-to-brown fat conversion. Significance: Increases in the number of beige cells in fat exerts beneficial metabolic actions. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Moran-Salvador E.,Hospital Clinic Esther Koplowitz Center | Titos E.,Hospital Clinic Esther Koplowitz Center | Titos E.,CIBER ISCIII | Rius B.,Hospital Clinic Esther Koplowitz Center | And 11 more authors.
Journal of Hepatology | Year: 2013

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.

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