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

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)598-606
Number of pages9
JournalCirculation Research
Volume99
Issue number6
DOIs
StatePublished - Sep 2006

Keywords

  • apoA-I
  • Coronary heart disease risk
  • HDL cholesterol
  • Hyperhomocysteinemia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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