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 beta-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.