Abstract
The mechanism underlying the dysregulation of cholesterol metabolism and inflammation in atherogenesis is not understood fully. Glycine N-methyltransferase (GNMT) has been implicated in hepatic lipid metabolism and the pathogenesis of liver diseases. However, little is known about the significance of GNMT in atherosclerosis. We showed the predominant expression of GNMT in foamy macrophages of mouse atherosclerotic aortas. Genetic deletion of GNMT exacerbated the hyperlipidemia, inflammation and development of atherosclerosis in apolipoprotein E-deficient mice. In addition, ablation of GNMT in macrophages aggravated oxidized low-density lipoprotein-mediated cholesterol accumulation in macrophage foam cells by downregulating the expression of reverse cholesterol transporters including ATP-binding cassette transporters-A1 and G1 and scavenger receptor BI. Furthermore, tumor necrosis factor-α-induced inflammatory response was promoted in GNMT-null macrophages. Collectively, our data suggest that GNMT is a crucial regulator in cholesterol metabolism and in inflammation, and contributes to the pathogenesis of atherosclerosis. This finding may reveal a potential therapeutic target for atherosclerosis.
Highlights
Glycine N-methyltransferase (GNMT)catalyzes the synthesis of sarcosine from glycine with S-adenosylmethionine (SAM) used as the methyl donor and thereby is an important regulator in the metabolism of SAM and S-adenosylhomocysteine (SAH) in the liver [1,2]
Because oxidized low-density lipoprotein (oxLDL) is a proatherogenic molecule in the development of atherosclerosis [14,15], we examined the effect of oxLDL on the expression of GNMT in macrophages
Because cellular cholesterol content in macrophage foam cells is dynamically regulated by oxLDL uptake and cholesterol efflux via SRs and reverse cholesterol transporters (RCTs), respectively [17,18,19,20,21,22], we examined the role of GNMT in regulating cholesterol homeostasis and the expression of SRs and RCTs
Summary
Glycine N-methyltransferase (GNMT)catalyzes the synthesis of sarcosine from glycine with S-adenosylmethionine (SAM) used as the methyl donor and thereby is an important regulator in the metabolism of SAM and S-adenosylhomocysteine (SAH) in the liver [1,2]. Considerable evidence supports that GNMT critically modulates the pathogenesis of liver diseases [6,7,8]. GNMT is a tumor suppressor and is downregulated in patients with liver cirrhosis or hepatocellular carcinoma (HCC) [7,8]. Clinical studies demonstrated metabolic abnormalities, including increased levels of serum methionine, SAM, and triglycerides, and hepatitislike symptoms in GNMT-deficient patients [9,10]. A GNMT-knockout (GNMT –/–) mouse model exhibited the same phenotype of liver diseases, including chronic hepatitis, steatosis, fibrosis and spontaneous HCC development [11,12,13]. The level of serum cholesterol is elevated in both GNMT-deficient patients and GNMT –/– mice, which implies that GNMT may be involved in the regulation of cholesterol metabolism [9,11]. Little is known about the role of GNMT in hypercholesterolemia and related diseases such as atherosclerosis
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