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Disrupting LXR? phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation

Gage, M C; Becares, N; Louie, R; Waddington, K E; Zhang, Y; Tittanegro, T H; Rodriguez-Lorenzo, S; Jathanna, A; Pourcet, B; Pello, O; De La Rosa, J V; Castrillo, A; Pineda-Torra, I


M C Gage

N Becares

R Louie

K E Waddington

Y Zhang

T H Tittanegro

S Rodriguez-Lorenzo

A Jathanna

B Pourcet

O Pello

J V De La Rosa

A Castrillo

I Pineda-Torra


Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors that play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust antiatherosclerotic transcriptional program in macrophages that can be affected by LXR? S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDL receptor (LDLR)-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high-fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXR?-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXR?-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXR? phosphorylation increases expression of phagocytic molecules, resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXR?-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this posttranslational modification. Overall, our findings demonstrate that LXR? phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.


Gage, M. C., Becares, N., Louie, R., Waddington, K. E., Zhang, Y., Tittanegro, T. H., …Pineda-Torra, I. (2018). Disrupting LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation. Proceedings of the National Academy of Sciences, 115(28), E6556-E6565.

Journal Article Type Article
Acceptance Date Jun 8, 2018
Publication Date Jul 10, 2018
Deposit Date Aug 23, 2019
Print ISSN 0027-8424
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 115
Issue 28
Pages E6556-E6565
Public URL