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.

Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease

“…In order to evaluate the role of an LRH-1 SUMO-defective pathway on intermediary liver metabolism, we subjected LRH-1 K289R mice, which exhibit partial gain of function of LRH-1, and control LRH-1 WT mice (9) to fasting-refeeding challenges in which mice were fasted and then refed for a period of 6 hours. We then evaluated the expression of metabolic genes in refed livers of both genotypes using microarray analysis.…”

“…ChIP analysis was performed as described previously, with minor modifications (9). ChIPed DNA was purified using the PCR Clean-up Extraction Kit (Macherey-Nagel), after which qPCR was performed as described previously (47).…”

“…On the other hand, treatment of mice with the LRH-1 agonist 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) protects animals from developing NAFLD and insulin resistance in genetic and dietary models of diabesity (7,8). To address this apparent contradictory role of LRH-1 in hepatic triglyceride metabolism, we chose to study lipogenesis in our recently described Lrh-1 K289R knockin mouse model (LRH-1 K289R mice), which displays selective gain of function of LRH-1 as a result of impaired SUMOylation at K289 (9).…”

Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists

“…In addition to a vital role during development (1,2), LRH-1 regulates many genes related to metabolism, proliferation, and cell survival. In the liver, LRH-1 regulates bile acid biosynthesis (3) and reverse cholesterol transport (4,5), affecting hepatic and circulating cholesterol levels. Glucose metabolism is also regulated by LRH-1 at several points, including GLUT-4-mediated transport (6) and glucose phosphorylation, the latter of which is essential for proper postprandial glucose sensing, flux through glycolysis and glycogenesis pathways, and de novo lipogenesis (7).…”

Nuclear Receptors in Vascular Biology

“…Recently, a particular post-translational modification of nuclear receptors, SUMOylation, was identified as critical for many trans-suppression pathways. Ligand dependent SUMOylation of PPAR or LXR mediates the antiinflammatory effects of these receptors by physically stabilizing pro-inflammatory transcription factors in a co-repressor complex [9], while SUMOylation of LRH-1 in the liver can lead to increased atherosclerosis in atheroprone mice due repression of reverse cholesterol transport [10].…”