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


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.
Hirano
Ken-ichi
K
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan. khirano@kb3.so-net.ne.jp
Ikegami
Chiaki
C
Tsujii
Ken-ichi
K
Zhang
Zhongyan
Z
Matsuura
Fumihiko
F
Nakagawa-Toyama
Yumiko
Y
Koseki
Masahiro
M
Masuda
Daisaku
D
Maruyama
Takao
T
Shimomura
Iichiro
I
Ueda
Yukihiko
Y
Yamashita
Shizuya
S
D000328:Adult; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000503:physiopathology; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011341:Probucol / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D051122:Scavenger Receptors, Class B / Q000235:genetics*; D013045:Species Specificity
D000924:Anticholesteremic Agents; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D003513:Cycloheximide; D011341:Probucol