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Article ; Online: Resolution of adipose tissue inflammation.

González-Périz, Ana / Clària, Joan

2010 Volume 10, Page(s) 832–856

Abstract: The presence of the so-called "low-grade" inflammatory state is recognized as a critical event in adipose tissue dysfunction in obesity. This chronic "low-grade" inflammation in white adipose tissue is powerfully augmented through the infiltration of ... ...

Abstract	The presence of the so-called "low-grade" inflammatory state is recognized as a critical event in adipose tissue dysfunction in obesity. This chronic "low-grade" inflammation in white adipose tissue is powerfully augmented through the infiltration of macrophages, which, together with adipocytes, perpetuate a vicious cycle of macrophage recruitment and secretion of free fatty acids and deleterious adipokines that predispose the development of obesity-related comorbidities, such as insulin resistance and nonalcoholic fatty liver disease. In the last decade, many factors have been identified that contribute to mounting uncontrolled inflammation in obese adipose tissue. Among them, bioactive lipid mediators derived from the cyclooxygenase and 5-lipoxygenase pathways, which convert the omega-6-polyunsaturated fatty acid (PUFA) arachidonic acid into potent proinflammatory eicosanoids (i.e., prostaglandins [PGs] and leukotrienes), have emerged. Interestingly, the same lipid mediators that initially trigger the inflammatory response also signal the termination of inflammation by stimulating the biosynthesis of anti-inflammatory and proresolving lipid autacoids. This review discusses the current status, characteristics, and progress in this class of "stop signals", including the lipoxins, which were the first identified omega-6 PUFA-derived lipid mediators with potent anti-inflammatory properties; the recently described omega-3 PUFA-derived lipid mediators resolvins and protectins; and the cyclopentenone PGs of the D series. Special emphasis is given to the participation of these bioactive lipid autacoids in the resolution of adipose tissue inflammation and in preventing the development of obesity-related complications.
MeSH term(s)	Adipokines/physiology ; Adipose Tissue/pathology ; Animals ; Fatty Acids, Omega-3/pharmacology ; Fatty Acids, Omega-6/pharmacology ; Humans ; Inflammation/pathology ; Inflammation/prevention & control
Chemical Substances	Adipokines ; Fatty Acids, Omega-3 ; Fatty Acids, Omega-6
Language	English
Publishing date	2010-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2075968-X
ISSN	1537-744X ; 1537-744X
ISSN (online)	1537-744X
ISSN	1537-744X
DOI	10.1100/tsw.2010.77
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Article ; Online: Resolution of Adipose Tissue Inflammation

Ana González-Périz / Joan Clària

The Scientific World Journal, Vol 10, Pp 832-

2010 Volume 856

Abstract: The presence of the so-called “low-grade” inflammatory state is recognized as a critical event in adipose tissue dysfunction in obesity. This chronic “low-grade” inflammation in white adipose tissue is powerfully augmented through the infiltration of ... ...

Abstract	The presence of the so-called “low-grade” inflammatory state is recognized as a critical event in adipose tissue dysfunction in obesity. This chronic “low-grade” inflammation in white adipose tissue is powerfully augmented through the infiltration of macrophages, which, together with adipocytes, perpetuate a vicious cycle of macrophage recruitment and secretion of free fatty acids and deleterious adipokines that predispose the development of obesity-related comorbidities, such as insulin resistance and nonalcoholic fatty liver disease. In the last decade, many factors have been identified that contribute to mounting uncontrolled inflammation in obese adipose tissue. Among them, bioactive lipid mediators derived from the cyclooxygenase and 5-lipoxygenase pathways, which convert the ω-6-polyunsaturated fatty acid (PUFA) arachidonic acid into potent proinflammatory eicosanoids (i.e., prostaglandins [PGs] and leukotrienes), have emerged. Interestingly, the same lipid mediators that initially trigger the inflammatory response also signal the termination of inflammation by stimulating the biosynthesis of anti-inflammatory and proresolving lipid autacoids. This review discusses the current status, characteristics, and progress in this class of “stop signals”, including the lipoxins, which were the first identified ω-6 PUFA–derived lipid mediators with potent anti-inflammatory properties; the recently described ω-3 PUFA–derived lipid mediators resolvins and protectins; and the cyclopentenone PGs of the D series. Special emphasis is given to the participation of these bioactive lipid autacoids in the resolution of adipose tissue inflammation and in preventing the development of obesity-related complications.
Keywords	Technology ; T ; Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2010-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
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Article ; Online: Resolvin D1 primes the resolution process initiated by calorie restriction in obesity-induced steatohepatitis.

Rius, Bibiana / Titos, Esther / Morán-Salvador, Eva / López-Vicario, Cristina / García-Alonso, Verónica / González-Périz, Ana / Arroyo, Vicente / Clària, Joan

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2014 Volume 28, Issue 2, Page(s) 836–848

Abstract: Insulin resistance and nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis combined with inflammation, are major sequelae of obesity. Currently, lifestyle modification (i.e., weight loss) is the first-line therapy for NASH. However, ... ...

Abstract	Insulin resistance and nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis combined with inflammation, are major sequelae of obesity. Currently, lifestyle modification (i.e., weight loss) is the first-line therapy for NASH. However, weight loss resolves steatosis but not inflammation. In this study, we tested the ability of resolvin D1 (RvD1), an anti-inflammatory and proresolving molecule, to promote the resolution initiated by calorie restriction in obese mice with NASH. Calorie restriction reduced adipose and liver weight (-56 and -13%, respectively; P<0.001), serum leptin and resistin levels, hepatic steatosis, and insulin resistance. In addition to these, mice receiving RvD1 during the dietary intervention showed increased adiponectin expression at both the mRNA and protein levels and reduced liver macrophage infiltration (-15%, P<0.01). Moreover, RvD1 skewed macrophages from an M1- to an M2-like anti-inflammatory phenotype, induced a specific hepatic miRNA signature (i.e., miR-219-5p and miR-199a-5p), and reduced inflammatory adipokine mRNA and protein expression and macrophage innate immune response. In precision-cut liver slices (PCLSs), which override the influence of circulating factors, RvD1 attenuated hypoxia-induced mRNA and protein expression of COX-2, IL-1β, IL-6, and CCR7. Of note, RvD1 anti-inflammatory actions were absent in macrophage-depleted PCLSs. In summary, RvD1 acts as a facilitator of the hepatic resolution process by reducing the inflammatory component of obesity-induced NASH.
MeSH term(s)	Animals ; Blotting, Western ; Caloric Restriction ; Docosahexaenoic Acids/genetics ; Docosahexaenoic Acids/metabolism ; Fatty Liver/diet therapy ; Fatty Liver/etiology ; Fatty Liver/metabolism ; Immunoenzyme Techniques ; Immunohistochemistry ; Insulin Resistance/physiology ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/genetics ; NF-kappa B/metabolism ; Obesity/complications ; Real-Time Polymerase Chain Reaction
Chemical Substances	MicroRNAs ; NF-kappa B ; resolvin D1 ; Docosahexaenoic Acids (25167-62-8)
Language	English
Publishing date	2014-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.13-235614
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Article ; Online: New insights into the role of macrophages in adipose tissue inflammation and Fatty liver disease: modulation by endogenous omega-3 Fatty Acid-derived lipid mediators.

Clària, Joan / González-Périz, Ana / López-Vicario, Cristina / Rius, Bibiana / Titos, Esther

Frontiers in immunology

2011 Volume 2, Page(s) 49

Abstract: Obesity is causally linked to a chronic state of "low-grade" inflammation in adipose tissue. Prolonged, unremitting inflammation in this tissue has a direct impact on insulin-sensitive tissues (i.e., liver) and its timely resolution is a critical step ... ...

Abstract	Obesity is causally linked to a chronic state of "low-grade" inflammation in adipose tissue. Prolonged, unremitting inflammation in this tissue has a direct impact on insulin-sensitive tissues (i.e., liver) and its timely resolution is a critical step toward reducing the prevalence of related co-morbidities such as insulin resistance and non-alcoholic fatty liver disease. This article describes the current state-of-the-art knowledge and novel insights into the role of macrophages in adipose tissue inflammation, with special emphasis on the progressive changes in macrophage polarization observed over the course of obesity. In addition, this article extends the discussion to the contribution of Kupffer cells, the liver resident macrophages, to metabolic liver disease. Special attention is given to the modulation of macrophage responses by omega-3-PUFAs, and more importantly by resolvins, which are potent anti-inflammatory and pro-resolving autacoids generated from docosahexaenoic and eicosapentaenoic acids. In fact, resolvins have been shown to work as endogenous "stop signals" in inflamed adipose tissue and to return this tissue to homeostasis by inducing a phenotypic switch in macrophage polarization toward a pro-resolving phenotype. Collectively, this article offers new views on the role of macrophages in metabolic disease and their modulation by endogenously generated omega-3-PUFA-derived lipid mediators.
Language	English
Publishing date	2011-10-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2011.00049
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Article ; Online: Association of a variant in the gene encoding for ERV1/ChemR23 with reduced inflammation in visceral adipose tissue from morbidly obese individuals.

López-Vicario, Cristina / Rius, Bibiana / Alcaraz-Quiles, José / González-Périz, Ana / Martínez-Puchol, Ana Isabel / Casulleras, Mireia / Duran-Güell, Marta / Ibarzabal, Ainitze / Corcelles, Ricard / Laguna-Fernández, Andrés / Back, Magnus / Titos, Esther / Clària, Joan

Scientific reports

2017 Volume 7, Issue 1, Page(s) 15724

Abstract: Obesity comorbidities are closely associated with chronic low-grade adipose tissue inflammation. A number of SNPs associated with inflammation has been identified, underscoring the impact of genetic determinants on this process. Here, we screened SNPs in ...

Abstract	Obesity comorbidities are closely associated with chronic low-grade adipose tissue inflammation. A number of SNPs associated with inflammation has been identified, underscoring the impact of genetic determinants on this process. Here, we screened SNPs in genes with pro-inflammatory (IL-1β, IL-6, STAT3 and JAK2), anti-inflammatory (IL-10 and SOCS3) and pro-resolving (ERV1/ChemR23) properties in 101 obese and 99 non-obese individuals. Among the SNPs analyzed, we identified that individuals carrying a C allele in the rs1878022 polymorphism of the ERV1/ChemR23 gene, which encodes for the receptor of the pro-resolving mediator RvE1, had increased ERV1/ChemR23 protein expression and reduced levels of the inflammatory cytokine IL-6 in adipose tissue. Moreover, patients carrying the C allele in homozygosity had lower plasma levels of IL-6, IFN-α2, IL-15, IL-1ra, IL-10, GM-CSF, G-CSF and VEGF and enhanced leukocyte responsiveness to RvE1. C-carriers also exhibited decreased TAG to HDL ratio, a surrogate marker of insulin resistance and a predictor of incident fatty liver. Finally, we confirmed in vivo that the ERV1/ChemR23 receptor regulates systemic and tissue inflammation since mice lacking ERV1/ChemR23 expression showed increased IL-6 levels in adipose tissue and peritoneal macrophages. Together, our study identified an ERV1/ChemR23 variant that protects patients with obesity from excessive inflammatory burden.
MeSH term(s)	Animals ; Female ; Gene Frequency/genetics ; Genetic Association Studies ; Homozygote ; Humans ; Inflammation/genetics ; Inheritance Patterns/genetics ; Interleukin-6/metabolism ; Intra-Abdominal Fat/pathology ; Liver/pathology ; Male ; Mice ; Middle Aged ; Models, Genetic ; Obesity, Morbid/genetics ; Omentum/pathology ; Polymorphism, Single Nucleotide/genetics ; Receptors, Chemokine/genetics
Chemical Substances	CMKLR1 protein, human ; Interleukin-6 ; Receptors, Chemokine
Language	English
Publishing date	2017-11-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-15951-z
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Article ; Online: Resolution of inflammation in obesity-induced liver disease.

Rius, Bibiana / López-Vicario, Cristina / González-Périz, Ana / Morán-Salvador, Eva / García-Alonso, Verónica / Clária, Joan / Titos, Esther

Frontiers in immunology

2012 Volume 3, Page(s) 257

Abstract: Low-grade inflammation in adipose tissue is recognized as a critical event in the development of obesity-related co-morbidities. This chronic inflammation is powerfully augmented through the infiltration of macrophages, which together with adipocytes, ... ...

Abstract	Low-grade inflammation in adipose tissue is recognized as a critical event in the development of obesity-related co-morbidities. This chronic inflammation is powerfully augmented through the infiltration of macrophages, which together with adipocytes, perpetuate a vicious cycle of inflammatory cell recruitment and secretion of free fatty acids and deleterious adipokines that predispose to greater incidence of metabolic complications. In the last decade, many factors have been identified to contribute to mounting unresolved inflammation in obese adipose tissue. Among them, pro-inflammatory lipid mediators (i.e., leukotrienes) derived from the omega-6 polyunsaturated arachidonic acid have been shown to play a prominent role. Of note, the same lipid mediators that initially trigger the inflammatory response also signal its termination by stimulating the formation of anti-inflammatory signals. Resolvins and protectins derived from the omega-3 polyunsaturated docosahexaenoic and eicosapentaenoic acids have emerged as a representative family of this novel class of autacoids with dual anti-inflammatory and pro-resolving properties that act as "stop-signals" of the inflammatory response. This review discusses the participation of these endogenous autacoids in the resolution of adipose tissue inflammation, with a special emphasis in the amelioration of obesity-related metabolic dysfunctions, namely insulin resistance and non-alcoholic fatty liver disease.
Language	English
Publishing date	2012-08-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2012.00257
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Article ; Online: An investigation of the resolution of inflammation (catabasis) in COPD.

Noguera, Aina / Gomez, Cristina / Faner, Rosa / Cosio, Borja / González-Périz, Ana / Clària, Joan / Carvajal, Angel / Agustí, Alvar

Respiratory research

2012 Volume 13, Page(s) 101

Abstract: Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an enhanced inflammatory response to smoking that persists despite quitting. The resolution of inflammation (catabasis) is a complex and highly regulated process where tissue ... ...

Abstract	Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an enhanced inflammatory response to smoking that persists despite quitting. The resolution of inflammation (catabasis) is a complex and highly regulated process where tissue resident macrophages play a key role since they phagocytose apoptotic cells (efferocytosis), preventing their secondary necrosis and the spill-over of their pro-inflammatory cytoplasmic content, and release pro-resolution and tissue repair molecules, such as TGFβ, VEGF and HGF. Because inflammation does not resolve in COPD, we hypothesized that catabasis may be abnormal in these patients. Methods: To explore this hypothesis, we studied lung tissue samples obtained at surgery from 21 COPD patients, 22 smokers with normal spirometry and 13 non-smokers controls. In these samples we used: (1) immunohistochemistry to assess the expression of CD44, CD36, VEGF and TGFβ in lung macrophages; (2) real time PCR to determine HGF, PPARγ, TGFβ, VEGF and MMP-9 gene expression; and, (3) ELISA to quantify lipoxin A4, a lipid mediator of catabasis. Results: We found that current and former smokers with COPD showed: (1) more inflammation (higher MMP-9 expression); (2) reduced macrophage surface expression of CD44, a key efferocytosis receptor; and, (3) similar levels of TGFβ, VEGF, HGF, PPARγ, and lipoxin A4 than smokers with normal spirometry, despite the presence of inflammation and disease. Conclusions: These results identify several potential abnormalities of catabasis in patients with COPD.
MeSH term(s)	Aged ; Cytokines/immunology ; Female ; Humans ; Immunologic Factors/immunology ; Lung/immunology ; Lung/pathology ; Macrophages, Alveolar/immunology ; Macrophages, Alveolar/pathology ; Male ; Middle Aged ; Pneumonia/immunology ; Pneumonia/pathology ; Pulmonary Disease, Chronic Obstructive/immunology ; Pulmonary Disease, Chronic Obstructive/pathology ; Smoking/immunology ; Smoking/pathology
Chemical Substances	Cytokines ; Immunologic Factors
Language	English
Publishing date	2012-11-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-9921
ISSN (online)	1465-993X
ISSN	1465-9921
DOI	10.1186/1465-9921-13-101
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Article ; Online: Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype.

Titos, Esther / Rius, Bibiana / González-Périz, Ana / López-Vicario, Cristina / Morán-Salvador, Eva / Martínez-Clemente, Marcos / Arroyo, Vicente / Clària, Joan

Journal of immunology (Baltimore, Md. : 1950)

2011 Volume 187, Issue 10, Page(s) 5408–5418

Abstract: We recently demonstrated that ω-3-polyunsaturated fatty acids ameliorate obesity-induced adipose tissue inflammation and insulin resistance. In this study, we report novel mechanisms underlying ω-3-polyunsaturated fatty acid actions on adipose tissue, ... ...

Abstract	We recently demonstrated that ω-3-polyunsaturated fatty acids ameliorate obesity-induced adipose tissue inflammation and insulin resistance. In this study, we report novel mechanisms underlying ω-3-polyunsaturated fatty acid actions on adipose tissue, adipocytes, and stromal vascular cells (SVC). Inflamed adipose tissue from high-fat diet-induced obese mice showed increased F4/80 and CD11b double-positive macrophage staining and elevated IL-6 and MCP-1 levels. Docosahexaenoic acid (DHA; 4 μg/g) did not change the total number of macrophages but significantly reduced the percentage of high CD11b/high F4/80-expressing cells in parallel with the emergence of low-expressing CD11b/F4/80 macrophages in the adipose tissue. This effect was associated with downregulation of proinflammatory adipokines in parallel with increased expression of IL-10, CD206, arginase 1, resistin-like molecule α, and chitinase-3 like protein, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. This shift was confined to the SVC fraction, in which secretion of Th1 cytokines (IL-6, MCP-1, and TNF-α) was blocked by DHA. Notably, resolvin D1, an anti-inflammatory and proresolving mediator biosynthesized from DHA, markedly attenuated IFN-γ/LPS-induced Th1 cytokines while upregulating arginase 1 expression in a concentration-dependent manner. Resolvin D1 also stimulated nonphlogistic phagocytosis in adipose SVC macrophages by increasing both the number of macrophages containing ingested particles and the number of phagocytosed particles and by reducing macrophage reactive oxygen species production. No changes in adipocyte area and the phosphorylation of hormone-sensitive lipase, a rate-limiting enzyme regulating adipocyte lipolysis, were observed. These findings illustrate novel mechanisms through which resolvin D1 and its precursor DHA confer anti-inflammatory and proresolving actions in inflamed adipose tissue.
MeSH term(s)	Adipose Tissue/immunology ; Adipose Tissue/pathology ; Animals ; Cell Polarity/immunology ; Disease Models, Animal ; Docosahexaenoic Acids/physiology ; Immunophenotyping ; Inflammation Mediators/physiology ; Macrophage Activation/immunology ; Macrophages/immunology ; Macrophages/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/immunology ; Obesity/metabolism ; Obesity/pathology ; Random Allocation ; Signal Transduction/immunology
Chemical Substances	Inflammation Mediators ; resolvin D1 ; Docosahexaenoic Acids (25167-62-8)
Language	English
Publishing date	2011-11-15
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1100225
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Article ; Online: Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis.

López-Vicario, Cristina / González-Périz, Ana / Rius, Bibiana / Morán-Salvador, Eva / García-Alonso, Verónica / Lozano, Juan José / Bataller, Ramón / Cofán, Montserrat / Kang, Jing X / Arroyo, Vicente / Clària, Joan / Titos, Esther

Gut

2014 Volume 63, Issue 2, Page(s) 344–355

Abstract: Objective: 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 ... ...

Abstract	Objective: 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. Design and results: Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, Δ-5 desaturase (Δ5D) and Δ6D in NASH. Increased expression of Δ5D and Δ6D 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 ω-6 and ω-3 pathways resulting in increased ω-6 to ω-3 ratio and reduced ω-3 index in human and mouse fatty livers. Restoration of hepatic ω-3 content in transgenic fat-1 mice expressing an ω-3 desaturase, which allows the endogenous conversion of ω-6 into ω-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 ω-3-enriched diet. A combined Δ5D/Δ6D 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 ω-3-treated hepatocytes. Conclusions: These findings indicate that impaired hepatic fatty acid desaturation and unbalanced ω-6 to ω-3 ratio play a role in the pathogenesis of NASH.
MeSH term(s)	Animals ; Chromatography, Gas ; Disease Models, Animal ; Fatty Acid Desaturases/metabolism ; Fatty Acids, Unsaturated/metabolism ; Fatty Liver/metabolism ; Gene Expression Profiling ; Hepatocytes/metabolism ; Humans ; Immunohistochemistry ; Linoleoyl-CoA Desaturase/metabolism ; Lipid Peroxidation ; Liver/metabolism ; Liver/pathology ; Male ; Mice ; Non-alcoholic Fatty Liver Disease ; Oligonucleotide Array Sequence Analysis ; Real-Time Polymerase Chain Reaction
Chemical Substances	Fatty Acids, Unsaturated ; Fatty Acid Desaturases (EC 1.14.19.-) ; Linoleoyl-CoA Desaturase (EC 1.14.19.3) ; delta-5 fatty acid desaturase (EC 1.14.99.-)
Language	English
Publishing date	2014-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2012-303179
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Article ; Online: Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells.

Morán-Salvador, Eva / Titos, Esther / Rius, Bibiana / González-Périz, Ana / García-Alonso, Verónica / López-Vicario, Cristina / Miquel, Rosa / Barak, Yaacov / Arroyo, Vicente / Clària, Joan

Journal of hepatology

2013 Volume 59, Issue 5, Page(s) 1045–1053

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 ... ...

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.
MeSH term(s)	Actins/metabolism ; Animals ; Carbon Tetrachloride/adverse effects ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/metabolism ; Chemical and Drug Induced Liver Injury/pathology ; Chemical and Drug Induced Liver Injury/physiopathology ; Disease Models, Animal ; Hepatic Stellate Cells/metabolism ; Hepatic Stellate Cells/pathology ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Inflammation/physiopathology ; Liver Cirrhosis/physiopathology ; Macrophages/metabolism ; Macrophages/pathology ; Mice ; Mice, Knockout ; PPAR gamma/deficiency ; PPAR gamma/genetics ; PPAR gamma/physiology ; Receptors, Cytoplasmic and Nuclear/deficiency ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/physiology ; Tissue Inhibitor of Metalloproteinase-1/metabolism
Chemical Substances	Actins ; PPAR gamma ; Receptors, Cytoplasmic and Nuclear ; Tissue Inhibitor of Metalloproteinase-1 ; Carbon Tetrachloride (CL2T97X0V0)
Language	English
Publishing date	2013-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2013.06.023
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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