NDLI: Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner.

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Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kim, Hong-pyo Nakahira, Kiichi Choi, Augustine M. K. Wong, Scott W. Hwang, Daniel H. Kwon, Myung-ja
Description	Author Affiliation: Wong SW ( Western Human Nutrition Research Center, the Agricultural Research Service (ARS)-United States Department of Agriculture, and Department of Nutrition, University of California, Davis, California 95616, USA.)
Abstract	The saturated fatty acids acylated on Lipid A of lipopolysaccharide (LPS) or bacterial lipoproteins play critical roles in ligand recognition and receptor activation for Toll-like Receptor 4 (TLR4) and TLR2. The results from our previous studies demonstrated that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4. However, the underlying mechanism has not been understood. Here, we report for the first time that the saturated fatty acid lauric acid induced dimerization and recruitment of TLR4 into lipid rafts, however, dimerization was not observed in non-lipid raft fractions. Similarly, LPS and lauric acid enhanced the association of TLR4 with MD-2 and downstream adaptor molecules, TRIF and MyD88, into lipid rafts leading to the activation of downstream signaling pathways and target gene expression. However, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, inhibited LPS- or lauric acid-induced dimerization and recruitment of TLR4 into lipid raft fractions. Together, these results demonstrate that lauric acid and DHA reciprocally modulate TLR4 activation by regulation of the dimerization and recruitment of TLR4 into lipid rafts. In addition, we showed that TLR4 recruitment to lipid rafts and dimerization were coupled events mediated at least in part by NADPH oxidase-dependent reactive oxygen species generation. These results provide a new insight in understanding the mechanism by which fatty acids differentially modulate TLR4-mediated signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	40
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2009-10-02
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Fatty Acids Pharmacology Membrane Microdomains Metabolism Protein Multimerization Drug Effects Reactive Oxygen Species Toll-Like Receptor 4 Chemistry Animals Cell Line Docosahexaenoic Acids Lauric Acids Lipopolysaccharides Lymphocyte Antigen 96 Mice NADPH Oxidase Antagonists & Inhibitors Protein Binding Protein Structure, Quaternary Protein Transport Signal Transduction Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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