title: Apolipoprotein A-I attenuates palmitate-mediated NF-κB activation by reducing Toll-like receptor-4 recruitment into lipid rafts.
abstract: While high-density lipoprotein (HDL) is known to protect against a wide range of inflammatory stimuli, its anti-inflammatory mechanisms are not well understood. Furthermore, HDL's protective effects against saturated dietary fats have not been previously described. In this study, we used endothelial cells to demonstrate that while palmitic acid activates NF-κB signaling, apolipoprotein A-I, (apoA-I), the major protein component of HDL, attenuates palmitate-induced NF-κB activation. Further, vascular NF-κB signaling (IL-6, MCP-1, TNF-α) and macrophage markers (CD68, CD11c) induced by 24 weeks of a diabetogenic diet containing cholesterol (DDC) is reduced in human apoA-I overexpressing transgenic C57BL/6 mice compared to age-matched WT controls. Moreover, WT mice on DDC compared to a chow diet display increased gene expression of lipid raft markers such as Caveolin-1 and Flotillin-1, and inflammatory Toll-like receptors (TLRs) (TLR2, TLR4) in the vasculature. However apoA-I transgenic mice on DDC show markedly reduced expression of these genes. Finally, we show that in endothelial cells TLR4 is recruited into lipid rafts in response to palmitate, and that apoA-I prevents palmitate-induced TLR4 trafficking into lipid rafts, thereby blocking NF-κB activation. Thus, apoA-I overexpression might be a useful therapeutic tool against vascular inflammation.
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington, United States of America.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Cheng
authors.forename: Priya
authors.initials: P
authors.lastname: Handa
authors.forename: Sanshiro
authors.initials: S
authors.lastname: Tateya
authors.forename: Jay
authors.initials: J
authors.lastname: Schwartz
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.forename: Poulami
authors.initials: P
authors.lastname: Mitra
authors.forename: John F
authors.initials: JF
authors.lastname: Oram
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014657:Vasculitis / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D016328:NF-kappa B; D010168:Palmitates; D051197:Toll-Like Receptor 4