Published online before print August 24, 2006, doi: 10.1161/01.RES.0000242559.42077.22
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© 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
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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