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 language||English (US)|
|Number of pages||9|
|State||Published - Sep 2006|
- Coronary heart disease risk
- HDL cholesterol
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine