title: ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes.
abstract: ATP11C is a homolog of ATP8B1, both of which catalyze the transport of phospholipids in biological membranes. Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis type1 in humans, which is characterized by a canalicular cholestasis. Mice deficient in ATP11C are characterized by a conjugated hyperbilirubinemia and an unconjugated hypercholanemia. Here, we have studied the hypothesis that ATP11C deficiency interferes with basolateral uptake of unconjugated bile salts, a process mediated by organic anion-transporting polypeptide (OATP) 1B2. ATP11C localized to the basolateral membrane of central hepatocytes in the liver lobule of control mice. In ATP11C-deficient mice, plasma total bilirubin levels were 6-fold increased, compared to control, of which ∼65% was conjugated and ∼35% unconjugated. Plasma total bile salts were 10-fold increased and were mostly present as unconjugated species. Functional studies in ATP11C-deficient mice indicated that hepatic uptake of unconjugated bile salts was strongly impaired whereas uptake of conjugated bile salts was unaffected. Western blotting and immunofluorescence analysis demonstrated near absence of basolateral bile salt uptake transporters OATP1B2, OATP1A1, OATP1A4, and Na(+) -taurocholate-cotransporting polypeptide only in central hepatocytes of ATP11C-deficient liver. In vivo application of the proteasome inhibitor, bortezomib, partially restored expression of these proteins, but not their localization. Furthermore, we observed post-translational down-regulation of ATP11C protein in livers from cholestatic mice, which coincided with reduced OATP1B2 levels.
  
  
  
  ATP11C is essential for basolateral membrane localization of multiple bile salt transport proteins in central hepatocytes and may act as a gatekeeper to prevent hepatic bile salt overload. Conjugated hyperbilirubinemia and unconjugated hypercholanemia and loss of OATP expression in ATP11C-deficient liver strongly resemble the characteristics of Rotor syndrome, suggesting that mutations in ATP11C can predispose to Rotor syndrome. (Hepatology 2016;64:161-174).
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Dirk R
authors.initials: DR
authors.lastname: de Waart
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Naik
authors.affiliation: Department of Biochemistry, University of Maringá, Paraná, Brazil.
authors.forename: Karina S
authors.initials: KS
authors.lastname: Utsunomiya
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Duijst
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Kam
authors.initials: K
authors.lastname: Ho-Mok
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: A Ruth
authors.initials: AR
authors.lastname: Bolier
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Hiralall
authors.affiliation: Liver Center Laboratory, Department of Medicine, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Piter J
authors.initials: PJ
authors.lastname: Bosma
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Coen C
authors.initials: CC
authors.lastname: Paulusma
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001663:Bilirubin / Q000097:blood; D015536:Down-Regulation; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D008565:Membrane Proteins; D012333:RNA, Messenger; C571241:TMEM30a protein, mouse; D046988:Proteasome Endopeptidase Complex; C000605549:ATP11C protein, mouse; D000251:Adenosine Triphosphatases; D001663:Bilirubin