SUMOylation-Dependent LRH-1/PROX1 Interaction Promotes Atherosclerosis by Decreasing Hepatic Reverse Cholesterol Transport

Sokrates Stein, Maaike H. Oosterveer, Chikage Mataki, Pan Xu, Vera Lemos, Rick Havinga, Claudia Dittner, Dongryeol Ryu, Keir J. Menzies, Xu Wang, Alessia Perino, Sander M. Houten, Frauke Melchior, Kristina Schoonjans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

49 Citations (Scopus)
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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 litter-mates 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.

Original languageEnglish
Pages (from-to)603-613
Number of pages11
JournalCell metabolism
Volume20
Issue number4
DOIs
Publication statusPublished - 7-Oct-2014

Keywords

  • LIVER RECEPTOR HOMOLOG-1
  • NUCLEAR RECEPTORS
  • IN-VIVO
  • LRH-1
  • EXPRESSION
  • MICE
  • GENE
  • LIVER-RECEPTOR-HOMOLOG-1
  • TRANSCRIPTION
  • METABOLISM

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