LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2.
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.
Department of Microbiology, NYU School of Medicine, New York, New York, United States of America.
Maryem A
MA
Hussein
Department of Microbiology, NYU School of Medicine, New York, New York, United States of America.
Elina
E
Shrestha
Department of Medicine, NYU School of Medicine, New York, New York, United States of America.
Mireille
M
Ouimet
Department of Medicine, NYU School of Medicine, New York, New York, United States of America.
Tessa J
TJ
Barrett
Department of Microbiology, NYU School of Medicine, New York, New York, United States of America.
Sarah
S
Leone
Department of Medicine, NYU School of Medicine, New York, New York, United States of America.
Kathryn J
KJ
Moore
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, 1 rue Laurent Fries, 67404, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France; Institut Clinique de la Souris, ICS, 1 rue Laurent Fries, 67404, Illkirch, France.
Yann
Y
Hérault
Department of Medicine, NYU School of Medicine, New York, New York, United States of America.
Edward A
EA
Fisher
Department of Microbiology, NYU School of Medicine, New York, New York, United States of America.
Michael J
MJ
Garabedian
D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis / Q000378:metabolism*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology; D001692:Biological Transport / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis*; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D006937:Hypercholesterolemia / Q000097:blood*; D008074:Lipoproteins / Q000096:biosynthesis / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D002784:Cholesterol; D008074:Lipoproteins; D000071518:Liver X Receptors; D008780:Methyltransferases; D057093:Orphan Nuclear Receptors; D011484:Protein-Arginine N-Methyltransferases; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C553397:PRMT2 protein, mouse