High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins.
To elucidate the anti-atherogenic effect of probucol, high-density lipoprotein (HDL) was isolated from probucol-treated patients (n = 14) and compared with that from control subjects (n = 12). The HDL obtained from probucol-treated patients was low in cholesteryl ester (CE) in comparison with that from control subjects (21.3 +/- 3.9 mol per cent vs. 27.6 +/- 3.2 mol% of total lipids. P < 0.001), and the peak diameters of patients' HDL were significantly smaller than those of control subjects on 4-30% non-denaturing polyacrylamide gradient gel electrophoresis (10.6 +/- 0.6 nm vs. 12.1 +/- 0.4 nm, P < 0.001). These data may be explained by the increased cholesteryl ester transfer protein (CETP) activities of probucol-treated patients (129 +/- 12% of control subjects, P < 0.001). The in vitro ability of HDL to remove CE from lipid-laden macrophages induced by incubation with acetylated low-density lipoprotein (Ac-LDL) was studied. The small and CE-poor HDL obtained from probucol-treated patients had a greater capacity to promote CE efflux from macrophages than did control HDL (59.8 +/- 6.9% vs. 44.2 +/- 5.4%, P < 0.01). Furthermore, the ability of HDL to promote cholesterol efflux correlated negatively with the CE content and particle diameter of HDL (r = -0.561 and r = -0.583 respectively; P < 0.01). When the inhibitory effect of HDL on the incorporation of [14C]-oleate into cellular cholesteryl ester was compared, the HDL from patients and control subjects inhibited CE formation to a similar extent. The enhanced ability of probucol-treated patients' HDL may, therefore, be involved in the acceleration of hydrolysis of the CE pool in macrophages. Taken together, we conclude that CETP plays a crucial role in making HDL more active in its anti-atherogenic function by reducing CE and making HDL smaller, and that probucol may enhance reverse cholesterol transport by activating CE transfer in vivo. The current study demonstrated, for the first time, that HDL modified by enhanced CETP activity in vivo is potentially anti-atherogenic.
Ishigami
M
M
Second Department of Internal Medicine, Osaka University Medical School, Japan.
Yamashita
S
S
Sakai
N
N
Hirano
K
K
Arai
T
T
Maruyama
T
T
Takami
S
S
Koyama
M
M
Kameda-Takemura
K
K
Matsuzawa
Y
Y
D000328:Adult; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000188:drug therapy*; D002352:Carrier Proteins / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism; D005260:Female; D006023:Glycoproteins; D006801:Humans; D008075:Lipoproteins, HDL / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use
D000924:Anticholesteremic Agents; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; D002784:Cholesterol; D011341:Probucol