title: rHDL administration increases reverse cholesterol transport in mice, but is not additive on top of ezetimibe or cholestyramine treatment.
abstract: OBJECTIVE
  Promoting reverse cholesterol transport (RCT) is a major atheroprotective property of HDL. The present study explored the effect of stimulating the first step of RCT (cholesterol efflux from macrophages) alone or in combination with stimulating the last step of RCT (fecal sterol excretion).
  
  
  RESULTS
  Reconstituted HDL (rHDL) was injected into wild-type mice either with or without administration of the cholesterol absorption inhibitor ezetimibe or the bile acid sequestrant cholestyramine. Single dose administration of rHDL (100 mg apoA-I/kg) resulted in an early (4 h) increase in plasma free cholesterol levels (p < 0.001), without affecting hepatic cholesterol levels or fecal mass sterol excretion. rHDL injection also increased [(3)H]cholesterol appearance in plasma at an early time-point (4 h) after intraperitoneal administration of [(3)H]cholesterol-labeled mouse macrophage foam cells and fecal radioactivity excretion indicating completed RCT was increased by 26% (p < 0.05). Ezetimibe treatment inhibited intestinal cholesterol absorption by 74% (p < 0.01), but also the bile acid sequestrant cholestyramine decreased cholesterol absorption significantly (24%, p < 0.01). Consequently, ezetimibe increased RCT 2.1-fold (p < 0.001) primarily within fecal neutral sterols, while cholestyramine increased RCT by 3.6-fold (p < 0.001), primarily within bile acids (p < 0.001), but also within neutral sterols (p < 0.001). However, no additive effects of both intestinal sterol uptake inhibitors were observed on top of rHDL administration.
  
  
  CONCLUSIONS
  These data demonstrate that increasing the first step of RCT by rHDL administration results in transient cholesterol mobilization from macrophages to plasma. This effect is not further enhanced by stimulating the last step of RCT, fecal sterol excretion.
authors.affiliation: F. Hoffmann La Roche Ltd. pRED, Cardiovascular & Metabolic Diseases, Basel, Switzerland.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Maugeais
authors.forename: Wijtske
authors.initials: W
authors.lastname: Annema
authors.forename: Denise
authors.initials: D
authors.lastname: Blum
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Mary
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism; D001384:Azetidines / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D002792:Cholestyramine Resin / Q000494:pharmacology*; D004357:Drug Synergism; D000069438:Ezetimibe; D005243:Feces; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D013261:Sterols / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001384:Azetidines; D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D013261:Sterols; D014280:Triglycerides; D002792:Cholestyramine Resin; D000069438:Ezetimibe