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(Circulation Research. 2006;99:598.)
© 2006 American Heart Association, Inc.

Molecular Medicine

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

Dan Liao, Hongmei Tan, Rutai Hui, Zhaohui Li, Xiaohua Jiang, John Gaubatz, Fan Yang, William Durante, Lawrence Chan, Andrew I. Schafer, Henry J. Pownall, Xiaofeng Yang, Hong Wang

From the Department of Medicine (D.L., Z.L., J.G., L.C., H.J.P., X.Y., H.W.), Baylor College of Medicine, Houston, Tex; Sun Yat-sen University Zhongshan Medical College (H.R.), Guangzhou, China; Fuwai Hospital (R.H.), Beijing, China; Department of Pharmacology (X.J., F.Y., X.Y., H.W.), Temple University School of Medicine, Philadelphia, Pa; Department of Medical Pharmacology and Physiology (W.D.), University of Missouri School of Medicine, Columbia; and Department of Medicine, University of Pennsylvania School of Medicine (A.I.S., X.Y., H.W.), Philadelphia, Pa.

Correspondence to Hong Wang, Temple University School of Medicine, Department of Pharmacology, 3420 N Broad St, Philadelphia, PA 19140. E-mail hongw{at}temple.edu

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 ß-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.

Key Words: apoA-I • coronary heart disease risk • HDL cholesterol • hyperhomocysteinemia

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