The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells.

[benign recurrent intrahepatic cholestasis]

Deficiency of the phospholipid flippase ATP 8 B 1 causes progressive familial intrahepatic cholestasis type 1 (PFIC 1 ) and benign recurrent intrahepatic cholestasis type 1 (BRIC 1 ). Apart from cholestasis , many patients also suffer from diarrhea of yet unknown etiology . Here we have studied the hypothesis that intestinal ATP 8 B 1 deficiency results in bile salt malabsorption as a possible cause of PFIC 1 /BRIC 1 diarrhea . Bile salt transport was studied in ATP 8 B 1 -depleted intestinal Caco-2 cells . Apical membrane localization was studied by a biotinylation approach . Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC 1 patients , of whom some had undergone biliary diversion or liver transplantation . Bile salt uptake by the apical sodium-dependent bile salt transporter SLC 10 A 2 was strongly impaired in ATP 8 B 1 -depleted Caco-2 cells . The reduced SLC 10 A 2 activity coincided with strongly reduced apical membrane localization , which was caused by impaired apical membrane insertion of SLC 10 A 2 . Moreover , we show that endogenous ATP 8 B 1 exists in a functional heterodimer with CDC 50 A in Caco-2 cells . Analyses of stool samples of post-transplant PFIC 1 patients demonstrated that bile salt content was not changed , whereas sodium and chloride concentrations were elevated and potassium levels were decreased . The ATP 8 B 1 -CDC 50 A heterodimer is essential for the apical localization of SLC 10 A 2 in Caco-2 cells . Diarrhea in PFIC 1 /BRIC 1 patients has a secretory origin to which SLC 10 A 2 deficiency may contribute . This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and /or reduced electrolyte resorption .