Abstract:
BACKGROUND:Ursodeoxycholic acid (UDCA) partly exerts choleretic effects by modifying the function of the bile salt export pump (Bsep, ABCB11). UDCA induces insertion of Bsep into the canalicular membrane of hepatocytes; however, underlying mechanisms remain unknown. We aimed to elucidate molecular mechanisms behind UDCA-induced Bsep activation. METHODS:We established MDCK II cells stably expressing both Bsep and Na(+)-taurocholate cotransporting polypeptide, and investigated the effect of UDCA on activity and protein expression of Bsep using these cells. We performed inhibitor study to know the molecules involved in UDCA-induced Bsep activation, and also tested the influence of UDCA on Bsep having a disease-associated mutation. RESULTS:UDCA activated Bsep in a dose-dependent manner. UDCA did not affect Bsep protein expression in whole cell lysates but increased its apical surface expression by extending the half-life from 2.4 to 5.0 h. This effect was specific to Bsep because UDCA did not affect other apical and basolateral proteins, and was independent of protein kinase A, adenylate cyclase, p38(MAPK), phosphatidylinositide 3-kinase, Ca(2+), and microtubules. NorUDCA activated Bsep similar to UDCA; however, cholic acid, taurocholic acid, and tauroUDCA had no effect. UDCA significantly increased the activity of Bsep with a benign recurrent intrahepatic cholestasis 2 mutation (A570T) but did not affect Bsep with a progressive familial intrahepatic cholestasis 2 mutation (G982R or D482G). CONCLUSIONS:We demonstrated that UDCA stabilizes Bsep protein in the apical membrane and increases its activity in MDCK II cells, presumably by retarding the endocytotic process.
journal_name
J Gastroenteroljournal_title
Journal of gastroenterologyauthors
Kagawa T,Orii R,Hirose S,Arase Y,Shiraishi K,Mizutani A,Tsukamoto H,Mine Tdoi
10.1007/s00535-013-0833-ysubject
Has Abstractpub_date
2014-05-01 00:00:00pages
890-9issue
5eissn
0944-1174issn
1435-5922journal_volume
49pub_type
杂志文章abstract:BACKGROUND:Although pancreatic duct guidewire placement (P-GW) for achieving selective biliary cannulation is reported to be effective in patients in whom endoscopic retrograde cholangiopancreatography (ERCP) is difficult, this technique entails a possible increased risk of post-ERCP pancreatitis. We conducted a prospe...
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