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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2422.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Probucol Enhances the Expression of Human Hepatic Scavenger Receptor Class B Type I, Possibly Through a Species-Specific Mechanism

Ken-ichi Hirano; Chiaki Ikegami; Ken-ichi Tsujii; Zhongyan Zhang; Fumihiko Matsuura; Yumiko Nakagawa-Toyama; Masahiro Koseki; Daisaku Masuda; Takao Maruyama; Iichiro Shimomura; Yukihiko Ueda; Shizuya Yamashita

From the Department of Metabolic Medicine (K.H., C.I., K.T., Z.Z., F.M., Y.-N.T., M.K., D.M., T.M., I.S., S.Y.), Graduate School of Medicine, Osaka University, and the Horizontal Medical Research Organization (Y.U.), Graduate School of Medicine, Kyoto University, Japan.

Correspondence to Ken-ichi Hirano, MD, PhD, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail khirano{at}kb3.so-net.ne.jp

Objective— Scavenger receptor class B type I (SR-BI) is a major receptor for high-density lipoproteins (HDL) in the liver, which is the terminus of reverse cholesterol transport. Overexpression of SR-BI attenuated experimental atherosclerosis in murine models, concomitant with a reduction in plasma HDL-cholesterol levels. Probucol is known to be a potent hypolipidemic drug to regress xanthoma formation and carotid atherosclerosis in conjunction with a marked reduction in HDL-cholesterol levels. The aim of the present study was to know the effect of probucol on the expression of SR-BI and the underlying mechanism.

Methods and Results— We found that probucol increased the expression of SR-BI proteins in in vitro human liver cells and an in vivo rabbit model, but not in wild-type C57Bl6 mice. The decay curve of SR-BI protein was markedly retarded in probucol-treated HepG2 cells in the presence of cycloheximide, indicating that probucol may stabilize human SR-BI protein. To determine the underlying mechanism for the observed species-specific effect, we conducted the following host-swap experiments, in which SR-BI was transfected or expressed in heterologous cells or hosts. Probucol did not increase human SR-BI protein in the liver of transgenic mice carrying the entire human SR-BI genome. Although probucol could stabilize even murine SR-BI, when transfected into a human cell line, HepG2, human SR-BI was not stabilized in a mouse hepatoma cell line, Hepa 1-6, treated with probucol.

Conclusion— Probucol enhances hepatic SR-BI protein expression, possibly through species-specific stabilization of the protein.

Probucol increases hepatic SR-BI, which seems to be attributable to a species-specific stabilization of the protein. Data of host-swap experiments indicate that this effect is unlikely to be the result of a direct interaction between probucol and SR-BI protein, but rather may be related to certain factors in human hepatocytes.

Key Words: atherosclerosis • high-density lipoprotein • probucol • reverse cholesterol transport • scavenger receptor class B type I

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