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Cell Metab. 2014 Oct 7;20(4):603-13. doi: 10.1016/j.cmet.2014.07.023. Epub 2014 Aug 28.

SUMOylation-dependent LRH-1/PROX1 interaction promotes atherosclerosis by decreasing hepatic reverse cholesterol transport.

Author information

1
Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
2
Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
3
Zentrum für Molekulare Biologie Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Joint Division Molecular Metabolic Control, Zentrum für Molekulare Biologie Heidelberg, Deutsches Krebsforschungszentrum (DKFZ) and University Hospital Heidelberg, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
4
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Zentrum für Molekulare Biologie Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
6
Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address: kristina.schoonjans@epfl.ch.

Abstract

Reverse cholesterol transport (RCT) is an antiatherogenic process in which excessive cholesterol from peripheral tissues is transported to the liver and finally excreted from the body via the bile. The nuclear receptor liver receptor homolog 1 (LRH-1) drives expression of genes regulating RCT, and its activity can be modified by different posttranslational modifications. Here, we show that atherosclerosis-prone mice carrying a mutation that abolishes SUMOylation of LRH-1 on K289R develop less aortic plaques than control littermates when exposed to a high-cholesterol diet. The mechanism underlying this atheroprotection involves an increase in RCT and its associated hepatic genes and is secondary to a compromised interaction of LRH-1 K289R with the corepressor prospero homeobox protein 1 (PROX1). Our study reveals that the SUMOylation status of a single nuclear receptor lysine residue can impact the development of a complex metabolic disease such as atherosclerosis.

PMID:
25176150
DOI:
10.1016/j.cmet.2014.07.023
[Indexed for MEDLINE]
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