Probucol enhances the expression of human hepatic scavenger receptor class B type I, possibly through a species-specific mechanism

Authors:
Hirano KI, Ikegami C, Tsujii KI, Zhang Z, Matsuura F, Nakagawa-Toyama Y, Koseki M, Masuda D, Maruyama T, Shimomura I, Ueda Y and Yamashita S
In:
Source: Arterioscler Thromb Vasc Biol
Publication Date: (2005)
Issue: 25(11): 2422-2427
Research Area:
Cancer Research/Cell Biology
Cardiovascular
Cells used in publication:
Hep G2
Species: human
Tissue Origin: liver
HEPA 1-6
Species: mouse
Tissue Origin: liver
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
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. CONCLUSIONS: Probucol enhances hepatic SR-BI protein expression, possibly through species-specific stabilization of the protein.