title: Hyperhomocysteinemia and high-density lipoprotein metabolism in cardiovascular disease.
abstract: Hyperhomocysteinemia (HHcy) is a significant and independent risk factor for cardiovascular disease (CVD) and the underlying mechanism is unclear. We and others have reported that homocysteine (Hcy) is inversely correlated with plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoA-I) in patients with coronary heart disease (CHD). We confirmed this negative correlation in mice with targeted deletions of the genes for apolipoprotein E (apoE) and cystathionine beta-synthase (CBS). Severe HHcy (plasma Hcy 210 micromol/L) accelerates spontaneous arthrosclerosis in the CBS(-/-)/apoE(-/-) mice, reduces the concentration of circulating HDL, apoA-I, and large HDL particles, inhibits HDL function, and enhances HDL-C clearance. We have demonstrated further that Hcy (0.5-2 mmol/L) reduces apoA-I protein synthesis and secretion, but not RNA transcription in mouse primary hepatocytes. A different mechanism was proposed based on studies using the HepG2 cells showing that Hcy (5-10 mmol/L) inhibits apoA-I transcription via peroxisome proliferator-activated receptor-alpha (PPARalpha)-inhibition-dependent and -independent mechanisms. These studies suggest that Hcy-induced HDL-C and apoA-I inhibition represent a novel mechanism by which Hcy induces atherosclerotic CVD.
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Liao
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
mesh_terms: D016632:Apolipoprotein A-I / Q000235:genetics; D002318:Cardiovascular Diseases / Q000150:complications / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D014176:Protein Biosynthesis; D051116:Receptors, Scavenger / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D051116:Receptors, Scavenger