title: Liver-specific induction of Abcg5 and Abcg8 stimulates reverse cholesterol transport in response to ezetimibe treatment.
abstract: OBJECTIVE
  Previous studies have shown ezetimibe treatment results in a 2-6-fold increase in reverse cholesterol transport (RCT). However, recent sterol balance studies question the role of biliary sterol secretion in RCT, and challenge the hypothesis that ezetimibe increases RCT through decreased absorption of biliary cholesterol in the intestine. We set out to determine whether ezetimibe may increase RCT by mechanisms that are independent of its well-established inhibition of intestinal cholesterol absorption.
  
  
  METHODS
  C57BL/6J, Npc1l1-KO, and/or Abcg8-KO mice were fed a chow diet with or without ezetimibe and fecal [(14)C]-neutral and [(14)C]-acidic sterols were measured to examine macrophage-to-feces RCT. We measured the expression of RCT related genes in the liver and jejunum in these mice. To confirm our significant gene expression findings, we utilized primary human hepatocytes cultured with or without a glucuronated metabolite of ezetimibe.
  
  
  RESULTS
  Our studies revealed that treatment with ezetimibe was associated with increased expression of hepatic Abcg5 and Abcg8. Ezetimibe did not directly affect expression in the liver, but this expression was due to the inhibition of intestinal cholesterol absorption. This conclusion was supported by the absence of an ABCG5/ABCG8 expression response to treatment with an ezetimibe metabolite in primary human hepatocytes. Finally, we found that the ezetimibe-dependent stimulation of RCT was attenuated in the absence of Abcg8.
  
  
  CONCLUSIONS
  Our study is the first to demonstrate ezetimibe treatment cooperatively stimulated macrophage-to-feces RCT by indirectly increasing liver Abcg5/Abcg8 expression in addition to its known suppression of intestinal cholesterol absorption.
authors: Genomic Medicine Institute, The Cleveland Clinic Foundation, Cleveland, OH, USA. Electronic address: altemuj@ccf.org.
authors: Jessica B
authors: JB
authors: Altemus
authors: Division of Endocrinology, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA; Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Shailendra B
authors: SB
authors: Patel
authors: Genomic Medicine Institute, The Cleveland Clinic Foundation, Cleveland, OH, USA.
authors: Ephraim
authors: E
authors: Sehayek
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000293:Adolescent; D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000378:metabolism
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001384:Azetidines; D008074:Lipoproteins; D002784:Cholesterol; D000069438:Ezetimibe
keywords: Atherosclerosis; Cholesterol absorption; Macrophage; Npc1l1; Sterol trafficking