LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2

Abstract

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.

Nutritionally Derived Metabolic Cues Typical of the Obese Microenvironment Increase Cholesterol Efflux Capacity of Adipose Tissue Macrophages

“…This was consistent with findings by Hussein et al. who demonstrated that d ‐glucose (25 m m ) suppressed LXR‐dependent expression of ABCA1 . Patel et al.…”

Phosphorylation of LXRα impacts atherosclerosis regression by modulating monocyte/macrophage trafficking

“…Regression in diabetic mice is associated with defective reduction of plaque CD68+ cells, suggesting increased macrophage retention or increased entry of monocytes despite lipid lowering (13,15). In a recent study we found that chronic high glucose significantly compromised LXR-dependent gene activation relative to normoglycemia in cultured bone marrow derived macrophages (16). Because of increased phosphorylation of LXRα at S196 in progressing plaques (12), we hypothesized that LXR function is impaired in diabetic mice through the same modification and contributes to the impaired regression.…”

Arginine Methylation: The Coming of Age

“…In mice, PRMTs are also involved in various metabolic processes associated with human disorders. PRMT2 null mice are resistant to dietary-induced obesity (Iwasaki et al, 2010), and PRMT2 is a glucose-sensitive protein (Hussein et al, 2015). PRMT3 was shown to regulate lipogenesis in MEFs, as a cofactor to the liver X receptor a (LXRa), and increased expression of PRMT3 correlates with non-alcoholic fatty liver disease (Kim et al, 2015a).…”