Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia.
Hyperalphalipoproteinemia (HALP) is caused by a variety of genetic and environmental factors. Among these, plasma cholesteryl ester transfer protein (CETP) deficiency is the most important and frequent cause of HALP in the Asian populations. CETP facilitates the transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to apolipoprotein (apo) B-containing lipoproteins, and is a key protein in the reverse cholesterol transport system. The deficiency of CETP causes various abnormalities in the concentration, composition, and function of both HDL and low density lipoprotein (LDL). The significance of CETP in terms of atherosclerosis had been controversial. However, the in vitro evidence showed large CE-rich HDL particles in CETP deficiency are defective in cholesterol efflux. Similarly, scavenger receptor BI (SR-BI) knockout mice show a marked increase in HDL-cholesterol but accelerated atherosclerosis in atherosclerosis-susceptible mice. Recent epidemiological studies in Japanese-Americans and in Omagari area where HALP subjects with the intron 14 splicing defect of CETP gene are markedly frequent, have demonstrated an increased incidence of coronary atherosclerosis in CETP-deficient patients. Thus, CETP deficiency is a state of impaired reverse cholesterol transport which may possibly lead to the development of atherosclerosis. The current review will focus on the molecular mechanisms and atherogenicity of HALP, especially CETP deficiency.
Yamashita
S
S
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan. shizu@imed2,med.osaka-u.ac.jp
Maruyama
T
T
Hirano
K
K
Sakai
N
N
Nakajima
N
N
Matsuzawa
Y
Y
D000818:Animals; D001054:Apolipoproteins A / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins; D006801:Humans; D006951:Hyperlipoproteinemias / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism
D001054:Apolipoproteins A; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL