title: Effect of sulfonylurea agents on reverse cholesterol transport in vitro and vivo.
abstract: OBJECTIVE
  Reverse cholesterol transport (RCT) is a critical mechanism for the anti-atherogenic property of HDL. The inhibitory effect of the sulfonylurea agent (SUA) glibenclamide on ATP binding-cassette transporter (ABC) A1 may decrease HDL function but it remains unclear whether it attenuates RCT in vivo. We therefore investigated how the SUAs glibenclamide and glimepiride affected the functionality of ABCA1/ABCG1 and scavenger receptor class B type I (SR-BI) expression in macrophages in vitro and overall RCT in vivo.
  
  
  METHODS
  RAW264.7, HEK293 and BHK-21 cells were used for in vitro studies. To investigate RCT in vivo, 3H-cholesterol-labeled and acetyl LDL-loaded RAW264.7 cells were injected into mice.
  
  
  RESULTS
  High dose (500µM) of glibenclamide inhibited ABCA1 function and apolipoprotein A-I (apoA-I)-mediated cholesterol efflux, and attenuated ABCA1 expression. Although glimepiride maintained apoA-I-mediated cholesterol efflux from RAW264.7 cells, like glibenclamide, it inhibited ABCA1-mediated cholesterol efflux from transfected HEK293 cells. Similarly, the SUAs inhibited SR-BI-mediated cholesterol efflux from transfected BHK-21 cells. High doses of SUAs increased ABCG1 expression in RAW264.7 cells, promoting HDL-mediated cholesterol efflux in an ABCG1-independent manner. Low doses (0.1-100 µM) of SUAs did not affect cholesterol efflux from macrophages despite dose-dependent increases in ABCA1/G1 expression. Furthermore, they did not change RCT or plasma lipid levels in mice.
  
  
  CONCLUSIONS
  High doses of SUAs inhibited the functionality of ABCA1/SR-BI, but not ABCG1. At lower doses, they had no unfavorable effects on cholesterol efflux or overall RCT in vivo. These results indicate that SUAs do not have adverse effects on atherosclerosis contrary to previous findings for glibenclamide.
authors.affiliation: Division of Anti-aging, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terao
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ogura
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.forename: Harumi
authors.initials: H
authors.lastname: Uto-Kondo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hisada
authors.forename: Hideki
authors.initials: H
authors.lastname: Ozasa
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Komatsu
authors.forename: Maki
authors.initials: M
authors.lastname: Iizuka
authors.forename: Shunpei
authors.initials: S
authors.lastname: Horii
authors.forename: Seibu
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D005905:Glyburide / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D005905:Glyburide