title: MD-2 binds cholesterol.
abstract: Cholesterol is a structural component of cellular membranes, which is transported from liver to peripheral cells in the form of cholesterol esters (CE), residing in the hydrophobic core of low-density lipoprotein. Oxidized CE (OxCE) is often found in plasma and in atherosclerotic lesions of subjects with cardiovascular disease. Our earlier studies have demonstrated that OxCE activates inflammatory responses in macrophages via toll-like receptor-4 (TLR4). Here we demonstrate that cholesterol binds to myeloid differentiation-2 (MD-2), a TLR4 ancillary molecule, which is a binding receptor for bacterial lipopolysaccharide (LPS) and is indispensable for LPS-induced TLR4 dimerization and signaling. Cholesterol binding to MD-2 was competed by LPS and by OxCE-modified BSA. Furthermore, soluble MD-2 in human plasma and MD-2 in mouse atherosclerotic lesions carried cholesterol, the finding supporting the biological significance of MD-2 cholesterol binding. These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis.
authors.affiliation: Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA.
authors.forename: Soo-Ho
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Gonen
authors.affiliation: Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA.
authors.forename: Suganya
authors.initials: S
authors.lastname: Viriyakosol
authors.affiliation: Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA. Electronic address: yumiller@ucsd.edu.
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry*; D051218:Lymphocyte Antigen 96 / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding
chemical_list: D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D002784:Cholesterol
keywords: Cholesterol; LPS; MD-2; TLR4