tlr4 and insulin resistancetlr4和胰岛素抵抗.pdfVIP

Hindawi Publishing Corporation Gastroenterology Research and Practice Volume 2010, Article ID 212563, 11 pages doi:10.1155/2010/212563 Review Article TLR4 and Insulin Resistance Jane J. Kim1, 2 and Dorothy D. Sears3 1 Department of Pediatrics, University of California, San Diego, CA 92093-0673, USA 2 Rady Children’s Hospital, San Diego, CA 92093-0673, USA 3 Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673, USA Correspondence should be addressed to Dorothy D. Sears, dsears@ Received 21 April 2010; Accepted 24 June 2010 Academic Editor: Ekihiro Seki Copyright © 2010 J. J. Kim and D. D. Sears. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4), involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) and endogenous ligands (e.g., free fatty acids) which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS) on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid