Document Detail


Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis.
MedLine Citation:
PMID:  23207144     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Progression from steatosis to steatohepatitic lesions is hypothesized to require a second hit. These lesions have been associated with increased oxidative stress, often ascribed to high levels of leptin and other proinflammatory mediators. Here we have examined the role of leptin in inducing oxidative stress and Kupffer cell activation in CCl4-mediated steatohepatitic lesions of obese mice.
METHODS: Male C57BL/6 mice fed with a high-fat diet (60%kcal) at 16 weeks were administered CCl₄ to induce steatohepatitic lesions. Approaches included use of immuno-spin trapping for measuring free radical stress, gene-deficient mice for leptin, p47 phox, iNOS and adoptive transfer of leptin primed macrophages in vivo.
RESULTS: Diet-induced obese (DIO) mice, treated with CCl4 increased serum leptin levels. Oxidative stress was significantly elevated in the DIO mouse liver, but not in ob/ob mice, or in DIO mice treated with leptin antibody. In ob/ob mice, leptin supplementation restored markers of free radical generation. Markers of free radical formation were significantly decreased by the peroxynitrite decomposition catalyst FeTPPS, the iNOS inhibitor 1400W, the NADPH oxidase inhibitor apocynin, or in iNOS or p47 phox-deficient mice. These results correlated with the decreased expression of TNF-alpha and MCP-1. Kupffer cell depletion eliminated oxidative stress and inflammation, whereas in macrophage-depleted mice, the adoptive transfer of leptin-primed macrophages significantly restored inflammation.
CONCLUSIONS: These results, for the first time, suggest that leptin action in macrophages of the steatotic liver, through induction of iNOS and NADPH oxidase, causes peroxynitrite-mediated oxidative stress thus activating Kupffer cells.
Authors:
Saurabh Chatterjee; Douglas Ganini; Erik J Tokar; Ashutosh Kumar; Suvarthi Das; Jean Corbett; Maria B Kadiiska; Michael P Waalkes; Anna Mae Diehl; Ronald P Mason
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-12-01
Journal Detail:
Title:  Journal of hepatology     Volume:  58     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-29     Completed Date:  2014-01-21     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  778-84     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 European Association for the Study of the Liver. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cytokines / metabolism
Disease Models, Animal
Fatty Liver / etiology,  metabolism*
Inflammation Mediators / metabolism
Kupffer Cells / metabolism*,  pathology
Leptin / metabolism*
Male
Mice
Mice, Inbred C57BL
NADPH Oxidase / metabolism
Nitric Oxide Synthase Type II / metabolism
Obesity / complications
Oxidative Stress*
Peroxynitrous Acid / metabolism
Grant Support
ID/Acronym/Agency:
4R00ES019875-02/ES/NIEHS NIH HHS; K99-R00//PHS HHS; R00 ES019875/ES/NIEHS NIH HHS; Z01 ES050139-13/ES/NIEHS NIH HHS; ZIA ES050139-18/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/Inflammation Mediators; 0/Leptin; 14691-52-2/Peroxynitrous Acid; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nos2 protein, mouse; EC 1.6.3.1/NADPH Oxidase
Comments/Corrections

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