Hyperhomocysteinemia Decreases Circulating High-Density Lipoprotein by Inhibiting Apolipoprotein A-I Protein Synthesis and Enhancing HDL Cholesterol Clearance

• Published in: Circulation research Vol. 99; no. 6; pp. 598 - 606
• Main Authors: Liao, Dan, Tan, Hongmei, Hui, Rutai, Li, Zhaohui, Jiang, Xiaohua, Gaubatz, John, Yang, Fan, Durante, William, Chan, Lawrence, Schafer, Andrew I, Pownall, Henry J, Yang, Xiaofeng, Wang, Hong
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 15-09-2006; Lippincott
• Subjects: Aged; Animals; Apolipoprotein A-I - antagonists & inhibitors; Apolipoprotein A-I - biosynthesis; Apolipoproteins E - deficiency; Biological and medical sciences; Biological Transport; Cardiology. Vascular system; Cells, Cultured; Cholesterol - metabolism; Cholesterol, HDL - metabolism; Coronary Artery Disease - etiology; Coronary heart disease; Cystathionine - deficiency; Fundamental and applied biological sciences. Psychology; Heart; Hepatocytes - metabolism; Homocysteine - blood; Humans; Hyperhomocysteinemia - blood; Hyperhomocysteinemia - metabolism; Lipoproteins, HDL - blood; Male; Medical sciences; Mice; Mice, Knockout; Middle Aged; Vertebrates: cardiovascular system; coronary heart disease risk; Cardiovascular disease; Lipids; Apolipoprotein; Clearance; Coronary heart disease; Cholesterol; HDL cholesterol; Vertebrata; Mammalia; Protein synthesis; Hyperhomocysteinemia; Circulatory system; Lipoprotein HDL; apoA-I
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000242559.42077.22

We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine β-synthase–/apolipoprotein E–deficient (CBS/apoE) mice. We observed that plasma homocysteine (Hcy) concentrations are negatively correlated with HDL-C and apolipoprotein A1 (apoA-I) in patients with CAD. We found the loss of large HDL particles, increased HDL-free cholesterol, and decreased HDL protein in CBS/apoE mice, and attenuated cholesterol efflux from cholesterol-loaded macrophages to plasma in CBS/apoE mice. ApoA-I protein was reduced in the plasma and liver, but hepatic apoA-I mRNA was unchanged in CBS/apoE mice. Moreover, Hcy (0.5 to 2 mmol/L) reduced the levels of apoA-I protein but not mRNA and inhibited apoA-1 protein synthesis in mouse primary hepatocytes. Further, plasma lecithin:cholesterol acyltransferase (LCAT) substrate reactivity was decreased, LCAT specific activity increased, and plasma LCAT protein levels unchanged in apoE/CBS mice. Finally, the clearance of plasma HDL cholesteryl ester, but not HDL protein, was faster in CBS/apoE mice, correlated with increased scavenger receptor B1, and unchanged ATP-binding cassette transporter A1 protein expression in the liver. These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance.