title: Targeting the ABCB4 gene to control cholesterol homeostasis.
abstract: BACKGROUND
  Multidrug resistance 3 (MDR3) P-glycoprotein is a lipid floppase that is encoded by the ATP-binding cassette sub-family B member 4 (ABCB4) gene and plays a crucial role in proper bile formation by transporting phosphatidylcholine across the canalicular plasma membrane of the hepatocyte into bile. The relevance of this function is underscored by the severe pathology that develops in patients with ABCB4 deficiency. This deficiency leads to the destruction of hepatocytes and cholangiocytes by bile salts, because their cytolytic action is not reduced by formation of mixed micelles with phospholipid.
  
  
  METHODS
  Evidence that phospholipid secretion into bile is also essential for biliary cholesterol secretion as cholesterol dissolves much better in mixed micelles of bile salts and phospholipid than in pure bile salt micelles. As a consequence, net biliary cholesterol secretion depends on the amount of phospholipid secreted and hence, the expression of ABCB4 indirectly determines biliary cholesterol output.
  
  
  CONCLUSIONS
  It can be argued that upregulation of the ABCB4 gene expression may not only be beneficial for liver pathology in patients with partial ABCB4 deficiency, but also for the prevention of gallstone formation and optimal cholesterol disposition in a much larger population.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl
authors.forename: Ronald Pj
authors.initials: RP
authors.lastname: Oude Elferink
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D018374:LLC-PK1 Cells; D051379:Mice; D013261:Sterols / Q000378:metabolism; D013552:Swine
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D013261:Sterols; D002784:Cholesterol; C095122:multidrug resistance protein 3