High cholesterol and diabetes are major risk factors for atherosclerosis, a disease characterized by the accumulation of lipid-laden macrophages in the artery walls. Regression of atherosclerosis is mediated in part by the Liver X Receptor (LXR), a transcription factor that induces the expression of genes involved in cholesterol transport and efflux. Importantly, regression of atherosclerosis is impaired in diabetes. I proposed that changes in glucose levels are important modulators of LXR gene expression. Using a mouse macrophage cell line (RAW 264.7) as well as primary bone marrow derived macrophages (BMDMs) cultured in normal or diabetes relevant high glucose conditions I found that high glucose inhibits the expression of ATP binding cassette transporter A1 (ABCA1), an LXR target that is central to the efflux of cholesterol from lipid-loaded macrophages. To begin to understand the mechanism whereby glucose imparts these differences, I performed a qPCR-based array that surveys all known chromatin modifying enzymes and found that Protein Arginine Methyltransferase 2 (PRMT2), a member of the Protein arginine methyltransferase family of enzymes that catalyze the N-methylation of proteins at arginine residues, was more highly expressed under normal compared to high glucose conditions. Using bone marrow derived macrophages from PRMT2 knockout mice I observed a decrease in ABCA1 compared to wild type cells and a corresponding decrease in ABCA1-mediated cholesterol efflux. These findings show an intriguing role for PRMT2 in modulating a gene involved in cholesterol homeostasis as well as the negative consequence of elevated glucose decreasing PRMT2 expression. Understanding the mechanisms whereby glucose impacts LXR gene regulatory functions could inform new approaches for treating diabetes and atherosclerosis.
|Advisor:||Garabedian, Michael J.|
|Commitee:||David, Gregory, Fisher, Edward, Rogatsky, Inez, Schneider, Robert|
|School:||New York University|
|School Location:||United States -- New York|
|Source:||DAI-B 76/08(E), Dissertation Abstracts International|
|Keywords:||Atherosclerosis, Cholesterol homeostasis, Diabetes, Transcription|
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