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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.


PubMed | Hospital Clinic Esther Koplowitz Center and University of Barcelona
Type: Journal Article | Journal: Adipocyte | Year: 2015

The formation of new adipocytes from precursor cells is a crucial aspect of normal adipose tissue function. During the adipogenic process, adipocytes differentiated from mesenchymal stem cells give rise to two main types of fat: white adipose tissue (WAT) characterized by the presence of adipocytes containing large unilocular lipid droplets, and brown adipose tissue (BAT) composed by multilocular brown adipocytes packed with mitochondria. WAT is not only important for energy storage but also as an endocrine organ regulating whole body homeostasis by secreting adipokines and other mediators, which directly impact metabolic functions in obesity. By contrast, BAT is specialized in dissipating energy in form of heat and has salutary effects in combating obesity and associated disorders. Unfortunately, WAT is the predominant fat type, whereas BAT is scarce and located in discrete pockets in adult humans. Luckily, another type of brown adipocytes, called beige or brite (brown-in-white) adipocytes, with similar functions to those of classical brown adipocytes has recently been identified in WAT. In this review, a close look is given into the role of bioactive lipid mediators in the regulation of adipogenesis, with a special emphasis on the role of the microsomal prostaglandin E (PGE) synthase-1, a terminal enzyme in PGE2 biosynthesis, as a key regulator of white-to-brown adipogenesis in WAT.


PubMed | Hospital Clinic Esther Koplowitz Center
Type: Journal Article | Journal: Journal of hepatology | Year: 2013

PPAR 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 plays a causative role in hepatocyte lipid deposition, contributing to the pathogenesis of hepatic steatosis. In this study, we investigated the role of PPAR in the inflammatory and fibrogenic response of the liver.Heterozygous floxed/null Cre/LoxP mice with targeted deletion of PPAR 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.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-, CXCL2, and IL-1 expression than Alb-Cre and control mice. The deleterious effects of PPAR 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 Massons trichrome staining, elevated hydroxyproline content and induced -SMA and TIMP-1 expression. Importantly, aP2-Cre mice with specific disruption of PPAR in HSCs, as confirmed by immunocytochemical analysis of individual liver cells, also showed exacerbated liver damage and fibrogenic response to CCl4.These data unveil anti-inflammatory and anti-fibrogenic roles for PPAR in non-parenchymal liver cells.


PubMed | Hospital Clinic Esther Koplowitz Center
Type: Journal Article | Journal: Gut | Year: 2014

The mechanisms underlying non-alcoholic steatohepatitis (NASH) are not completely elucidated. In the current study we integrated gene expression profiling of liver biopsies from NASH patients with translational studies in mouse models of steatohepatitis and pharmacological interventions in isolated hepatocytes to identify new molecular targets in NASH.Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, -5 desaturase (5D) and 6D in NASH. Increased expression of 5D and 6D at both mRNA and protein level were confirmed in livers from mice with high-fat diet-induced obesity and NASH. Gas chromatography analysis revealed impaired desaturation fluxes toward the -6 and -3 pathways resulting in increased -6 to -3 ratio and reduced -3 index in human and mouse fatty livers. Restoration of hepatic -3 content in transgenic fat-1 mice expressing an -3 desaturase, which allows the endogenous conversion of -6 into -3 fatty acids, produced a significant reduction in hepatic insulin resistance, steatosis, macrophage infiltration, necroinflammation and lipid peroxidation, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were mostly reproduced by feeding obese mice with an exogenous -3-enriched diet. A combined 5D/6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and -3-treated hepatocytes.These findings indicate that impaired hepatic fatty acid desaturation and unbalanced -6 to -3 ratio play a role in the pathogenesis of NASH.

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