| Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. | |
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MedLine Citation:
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PMID: 19699298 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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While adipose tissue-associated macrophages contribute to development of chronic inflammation and insulin resistance of obesity, little is known about the role of hepatic Kupffer cells in this environment. Here we address the impact of Kupffer cell ablation using clodronate-encapsulated liposome depletion in a diet-induced obese (DIO) and insulin resistant mouse model. Hepatic expression of macrophage markers measured by realtime RT-PCR remained unaltered in DIO mice despite characteristic expansion of adipose tissue-associated macrophages. DIO mouse livers displayed increased expression of alternative activation markers but unaltered proinflammatory cytokine expression when compared to lean mice. Kupffer cell ablation reduced hepatic anti-inflammatory cytokine IL-10 mRNA expression in lean and DIO mice by 95% and 84%, respectively. Despite decreased hepatic IL-6 gene expression after ablation in lean and DIO mice, hepatic STAT3 phosphorylation, Socs3 and acute phase protein mRNA expression increased. Kupffer cell ablation in DIO mice resulted in additional hepatic triglyceride accumulation and a 30-40% reduction in hepatic insulin receptor autophosphorylation and Akt activation. Implicating systemic loss of IL-10, high-fat-fed IL-10 knockout mice also displayed increased hepatic STAT3 signaling and hepatic triglyceride accumulation. Insulin signaling was not altered, however. In conclusion, Kupffer cells are a major source of hepatic IL-10 expression, the loss of which is associated with increased STAT3-dependent signaling and steatosis. One or more additional factors appear to be required, however, for the Kupffer cell-dependent protective effect on insulin receptor signaling in DIO mice. |
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Authors:
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Alicia H Clementi; Allison M Gaudy; Nico van Rooijen; Robert H Pierce; Robert A Mooney |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-08-20 |
Journal Detail:
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Title: Biochimica et biophysica acta Volume: 1792 ISSN: 0006-3002 ISO Abbreviation: Biochim. Biophys. Acta Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-10-19 Completed Date: 2009-12-23 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 0217513 Medline TA: Biochim Biophys Acta Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1062-72 Citation Subset: IM |
Affiliation:
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Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adipose Tissue
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metabolism,
pathology Animals Bone Density Conservation Agents / adverse effects, pharmacology Clodronic Acid / adverse effects, pharmacology Diet / adverse effects* Disease Models, Animal Fatty Liver / chemically induced, metabolism*, pathology Gene Expression Regulation / drug effects Inflammation Mediators / metabolism Insulin / metabolism* Insulin Resistance Interleukin-10 / metabolism Interleukin-6 / metabolism Kupffer Cells / metabolism*, pathology Liposomes Macrophages / metabolism, pathology Male Mice Obesity / chemically induced, metabolism*, pathology Phosphorylation / drug effects Proto-Oncogene Proteins c-akt / metabolism RNA, Messenger Receptor, Insulin / metabolism STAT3 Transcription Factor / metabolism* Signal Transduction* Suppressor of Cytokine Signaling Proteins / metabolism Triglycerides / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK060732-04/DK/NIDDK NIH HHS; R01-DK060732/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bone Density Conservation Agents; 0/Inflammation Mediators; 0/Interleukin-6; 0/Liposomes; 0/RNA, Messenger; 0/STAT3 Transcription Factor; 0/Socs3 protein, mouse; 0/Stat3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 0/Triglycerides; 10596-23-3/Clodronic Acid; 11061-68-0/Insulin; 130068-27-8/Interleukin-10; EC 2.7.10.1/Receptor, Insulin; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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