| The effects of palmitate on hepatic insulin resistance are mediated by NADPH Oxidase 3-derived reactive oxygen species through JNK and p38MAPK pathways. | |
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MedLine Citation:
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PMID: 20647313 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Elevated plasma free fatty acid (FFA) levels in obesity may play a pathogenic role in the development of insulin resistance. However, molecular mechanisms linking FFA to insulin resistance remain poorly understood. Oxidative stress acts as a link between FFA and hepatic insulin resistance. NADPH oxidase 3 (NOX3)-derived reactive oxygen species (ROS) may mediate the effect of TNF-α on hepatocytes, in particular the drop in cellular glycogen content. In the present study, we define the critical role of NOX3-derived ROS in insulin resistance in db/db mice and HepG2 cells treated with palmitate. The db/db mice displayed increased serum FFA levels, excess generation of ROS, and up-regulation of NOX3 expression, accompanied by increased lipid accumulation and impaired glycogen content in the liver. Similar results were obtained from palmitate-treated HepG2 cells. The exposure of palmitate elevated ROS production and NOX3 expression and, in turn, increased gluconeogenesis and reduced glycogen content in HepG2 cells. We found that palmitate induced hepatic insulin resistance through JNK and p38(MAPK) pathways, which are rescued by siRNA-mediated NOX3 reduction. In conclusion, our data demonstrate a critical role of NOX3-derived ROS in palmitate-induced insulin resistance in hepatocytes, indicating that NOX3 is the predominant source of palmitate-induced ROS generation and that NOX3-derived ROS may drive palmitate-induced hepatic insulin resistance through JNK and p38(MAPK) pathways. |
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Authors:
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Dan Gao; Shanwei Nong; Xiuqing Huang; Yonggang Lu; Hongye Zhao; Yajun Lin; Yong Man; Shu Wang; Jiefu Yang; Jian Li |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-20 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-20 Completed Date: 2010-10-21 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 29965-73 Citation Subset: IM |
Affiliation:
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Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Gene Expression Regulation, Enzymologic / drug effects, genetics Glycogen / genetics, metabolism Hep G2 Cells Hepatocytes / metabolism* Humans Insulin Resistance* Liver / metabolism MAP Kinase Kinase 4 / genetics, metabolism* MAP Kinase Signaling System / drug effects, genetics Membrane Proteins / biosynthesis*, genetics Mice NADPH Oxidase / biosynthesis*, genetics Obesity / genetics, metabolism Oxidative Stress / drug effects, genetics Palmitic Acid / metabolism, pharmacology* Reactive Oxygen Species / metabolism* Tumor Necrosis Factor-alpha / genetics, metabolism p38 Mitogen-Activated Protein Kinases / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Membrane Proteins; 0/Reactive Oxygen Species; 0/Tumor Necrosis Factor-alpha; 57-10-3/Palmitic Acid; 9005-79-2/Glycogen; EC 1.6.-/Nox3 protein, mouse; EC 1.6.3.-/Nox3 protein, human; EC 1.6.3.1/NADPH Oxidase; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.12.2/MAP Kinase Kinase 4 |
| Comments/Corrections | |
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