title: SUMOylation-dependent LRH-1/PROX1 interaction promotes atherosclerosis by decreasing hepatic reverse cholesterol transport.
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.
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Sokrates
authors.initials: S
authors.lastname: Stein
authors.affiliation: Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Chikage
authors.initials: C
authors.lastname: Mataki
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Pan
authors.initials: P
authors.lastname: Xu
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Vera
authors.initials: V
authors.lastname: Lemos
authors.affiliation: Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dittner
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Keir J
authors.initials: KJ
authors.lastname: Menzies
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Zentrum für Molekulare Biologie Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Melchior
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address: kristina.schoonjans@epfl.ch.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D016415:Sequence Alignment; D058207:Sumoylation; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D002784:Cholesterol