Shrestha, E;
Voisin, M;
Barret, T;
Nishi, H;
Cantor, D;
Hissein, M;
David, G;
... Garabedian, M; + view all
(2018)
Phosphorylation of LXRα impacts atherosclerosis regression by modulating monocyte trafficking.
bioRxiv
10.1101/363366.
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Abstract
LXRα activation in macrophages enhances regression of atherosclerotic plaques in mice by regulating genes crucial for cholesterol efflux, cell motility and inflammation. Diabetes, however, impairs plaque regression in mice. LXRα is phosphorylated at serine 198 (pS198), which affects the expression of genes controlling inflammation, lipid metabolism and cell movement. We hypothesize that LXRα function is affected by hyperglycemia through changes in LXRα pS198. Indeed, macrophages cultured in diabetes relevant high glucose versus normal glucose display alterations in LXR-dependent gene expression and increased LXRα pS198. We therefore examined the consequence of disrupting LXRα phosphorylation (S196A in mouse LXRα) during regression of atherosclerosis in normal and diabetic mice. We find that phosphorylation deficient LXRα S196A reduces macrophage retention in plaques in diabetes, which is predicted to be anti-atherogenic and enhance plaque regression. However, this favorable effect on regression is masked by increased monocyte infiltration in the plaque attributed to leukocytosis in LXRα S196A mice. RNA-seq of plaque macrophages from diabetic S196A mice shows increased expression of chemotaxis and decreased expression of cell adhesion genes, consistent with reduced macrophage retention by LXRα S196A. Thus, the non-phosphorylated form of LXRα precludes macrophage retention in the plaque. Our study provides the first evidence for a physiological role of LXRα phosphorylation in modulating atherosclerosis regression. Compounds that prevent LXRα phosphorylation or ligands that induce the conformation of non-phosphorylated LXRα may selectively enhance macrophage emigration from atherosclerotic plaques.
| Type: | Article |
|---|---|
| Title: | Phosphorylation of LXRα impacts atherosclerosis regression by modulating monocyte trafficking |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1101/363366 |
| Publisher version: | https://doi.org/10.1101/363366 |
| Language: | English |
| Additional information: | The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. |
| Keywords: | LXR, Phosphorylation, Atherosclerosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10060720 |
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