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

Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2422-7. doi: 10.1161/01.ATV.0000185834.98941.3d. Epub 2005 Sep 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Anticholesteremic Agents / pharmacology*
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / physiopathology
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Cycloheximide / pharmacology
  • Disease Models, Animal
  • Gene Expression / drug effects
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Hepatocytes / physiology
  • Humans
  • Liver Neoplasms
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Probucol / pharmacology*
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / analysis
  • Rabbits
  • Scavenger Receptors, Class B / genetics*
  • Species Specificity

Substances

  • Anticholesteremic Agents
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • Cycloheximide
  • Probucol