LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2.
Fiche publication
Date publication
janvier 2015
Journal
PloS one
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann
Tous les auteurs :
Hussein MA, Shrestha E, Ouimet M, Barrett TJ, Leone S, Moore KJ, Hérault Y, Fisher EA, Garabedian MJ
Lien Pubmed
Résumé
High cholesterol and diabetes are major risk factors for atherosclerosis. Regression of atherosclerosis is mediated in part by the Liver X Receptor (LXR) through the induction of genes involved in cholesterol transport and efflux. In the context of diabetes, regression of atherosclerosis is impaired. We proposed that changes in glucose levels modulate LXR-dependent gene expression. Using a mouse macrophage cell line (RAW 264.7) and primary bone marrow derived macrophages (BMDMs) cultured in normal or diabetes relevant high glucose conditions we found that high glucose inhibits the LXR-dependent expression of ATP-binding cassette transporter A1 (ABCA1), but not ABCG1. To probe for this mechanism, we surveyed the expression of a host of chromatin-modifying enzymes and found that Protein Arginine Methyltransferase 2 (PRMT2) was reduced in high compared to normal glucose conditions. Importantly, ABCA1 expression and ABCA1-mediated cholesterol efflux were reduced in Prmt2-/- compared to wild type BMDMs. Monocytes from diabetic mice also showed decreased expression of Prmt2 compared to non-diabetic counterparts. Thus, PRMT2 represents a glucose-sensitive factor that plays a role in LXR-mediated ABCA1-dependent cholesterol efflux and lends insight to the presence of increased atherosclerosis in diabetic patients.
Mots clés
ATP Binding Cassette Transporter 1, biosynthesis, ATP Binding Cassette Transporter, Sub-Family G, Member 1, ATP-Binding Cassette Transporters, biosynthesis, Animals, Atherosclerosis, pathology, Biological Transport, genetics, Blood Glucose, analysis, Cell Line, Cholesterol, blood, Diabetes Mellitus, Experimental, Hypercholesterolemia, blood, Lipoproteins, biosynthesis, Liver X Receptors, Macrophages, metabolism, Male, Methyltransferases, metabolism, Mice, Mice, Inbred C57BL, Orphan Nuclear Receptors, biosynthesis, Protein-Arginine N-Methyltransferases
Référence
PLoS ONE. 2015 ;10(8):e0135218