[PDF][PDF] Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism

A Castrillo, SB Joseph, SA Vaidya, M Haberland… - Molecular cell, 2003 - cell.com
A Castrillo, SB Joseph, SA Vaidya, M Haberland, AM Fogelman, G Cheng, P Tontonoz
Molecular cell, 2003cell.com
The liver X receptors (LXR) α and β are regulators of cholesterol metabolism and
determinants of atherosclerosis susceptibility. Viral and bacterial pathogens have long been
suspected to be modulators of atherogenesis; however, mechanisms linking innate immunity
to cholesterol metabolism are poorly defined. We demonstrate here that pathogens interfere
with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway.
Activation of Toll-like receptors (TLR) 3 and 4 by microbial ligands blocks the induction of …
Abstract
The liver X receptors (LXR) α and β are regulators of cholesterol metabolism and determinants of atherosclerosis susceptibility. Viral and bacterial pathogens have long been suspected to be modulators of atherogenesis; however, mechanisms linking innate immunity to cholesterol metabolism are poorly defined. We demonstrate here that pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway. Activation of Toll-like receptors (TLR) 3 and 4 by microbial ligands blocks the induction of LXR target genes including ABCA1 in cultured macrophages as well as in aortic tissue in vivo. As a consequence of these transcriptional effects, TLR3/4 ligands strongly inhibit cholesterol efflux from macrophages. Crosstalk between LXR and TLR signaling is mediated by IRF3, a specific effector of TLR3/4 that inhibits the transcriptional activity of LXR on its target promoters. These findings highlight a common mechanism whereby bacterial and viral pathogens may modulate macrophage cholesterol metabolism and cardiovascular disease.
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