title: Pharmacologic suppression of hepatic ATP-binding cassette transporter 1 activity in mice reduces high-density lipoprotein cholesterol levels but promotes reverse cholesterol transport.
abstract: BACKGROUND
  The role of hepatic ATP-binding cassette transporter 1 (ABCA1) in maintaining plasma high density lipoprotein cholesterol (HDL-C) levels is well established, but its role in reverse cholesterol transport (RCT) is unclear. Probucol is a compound that reduces HDL-C levels but also reduces atherosclerosis in animal models and xanthomas in humans. The aim of the present study was to test the hypothesis that probucol inhibits hepatic ABCA1 activity, thereby reducing HDL-C levels but promoting RCT from macrophages.
  
  
  RESULTS
  Wild-type (WT) C57BL/6 mice and scavenger receptor class B type I (SR-BI) knockout mice were fed a chow diet containing 0.5% probucol or normal chow for 2 weeks. In WT mice, probucol, despite decreasing HDL-C by >80%, effectively maintained macrophage RCT. In SR-BI knockout mice, probucol also substantially reduced HDL-C but significantly increased macrophage RCT. Furthermore, probucol significantly enhanced the excretion of HDL-derived cholesterol into feces in both WT and SR-BI knockout mice. Probucol inhibited ABCA1-dependent cholesterol efflux from mouse primary hepatocytes, and this effect was shown to be responsible for the effect of probucol on increasing the fecal excretion of HDL-derived cholesterol in vivo.
  
  
  CONCLUSIONS
  We demonstrate that pharmacological inhibition of hepatic ABCA1 activity with probucol reduced HDL-C levels but promoted RCT through diversion of HDL-derived cholesterol from efflux back into plasma instead to excretion in the bile. These results explain the beneficial effects of probucol on atherosclerosis and xanthomas despite its HDL-lowering effects and suggest that inactivation of hepatic ABCA1 leads to increased RCT despite reducing plasma HDL-C levels.
authors.affiliation: Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanigawa
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Yohei
authors.initials: Y
authors.lastname: Komaru
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Billheimer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control; D001659:Biliary Tract / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011341:Probucol / Q000494:pharmacology; D014973:Xanthomatosis / Q000378:metabolism / Q000517:prevention & control
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D011341:Probucol