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

Author(s):Show less -

Gage, M. C. ^[1] ; Becares, N. ^[1] ; Louie, R. ^[1] ; Waddington, K. E. ^[1] ; Zhang, Y. ^[1] ; Tittanegro, T. H. ^[1] ; Rodriguez-Lorenzo, S. ^[1] ; Jathanna, A. ^[1] ; Pourcet, B. ^{[1, 2]} ; Pello, O. M. ^{[1, 3]} ; De la Rosa, J. V. ^{[4, 5]} ; Castrillo, A. ^{[4, 5]} ; Pineda-Torra, I. ^[1]

Affiliation

^[1] UCL, Ctr Clin Pharmacol, Div Med, London WC1 E6JF - England

^[2] Univ Lille, European Genom Inst Diabet, France & Inst Pasteur Lille, INSERM, UMR 1011, CHU Lille, F-59000 Lille - France

^[3] Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, John Goldman Ctr Cellular Therapy, London W12 0HS - England

^[4] Univ Autonoma Madrid, Inst Invest Biomed Alberto Sols, CSIC, Madrid 28029 - Spain

^[5] Univ Las Palmas Gran Canaria, Grp Invest Medio Ambiente & Salud, Inst Univ Invest Biomed & Sanitarias, Unidad Asociada, CSIC, Unidad Biomed, Las Palmas Gran Canaria 35016 - Spain

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 115, n. 28, p. E6556-E6565, JUL 10 2018.
• Web of Science Citations: 5

Abstract

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 anti-atherosclerotic transcriptional program in macrophages that can be affected by LXRa 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 LXRa-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXRa-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXRa 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 LXRa-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 LXRa phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways. (AU)

• FAPESP's process: 17/12314-0 - Inhibition of LXR alpha phosphorylation: evaluating target gene expression effects and LXR alpha and PPAR gamma crosstalk
• Grantee: Thaís Helena Tittanegro
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree