title: Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance.
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 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.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Liao
authors.forename: Hongmei
authors.initials: H
authors.lastname: Tan
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.forename: John
authors.initials: J
authors.lastname: Gaubatz
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: William
authors.initials: W
authors.lastname: Durante
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Schafer
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Pownall
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
mesh_terms: D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001057:Apolipoproteins E / Q000172:deficiency; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000209:etiology; D003540:Cystathionine / Q000172:deficiency; D022781:Hepatocytes / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D006710:Homocysteine; D003540:Cystathionine; D002784:Cholesterol