title: Ursodeoxycholic acid stimulates the formation of the bile canalicular network.
abstract: Ursodeoxycholic acid (UDCA) is a hepatoprotective bile acid used in the treatment of chronic liver diseases. Although several pharmacological effects, including choleresis and inhibition of apoptosis, have been proposed, the impact of UDCA on hepatic structure is not well understood. Here, the influence of UDCA on bile canalicular (BC) morphology was evaluated in vitro in immortalized rat hepatocytes (McA-RH 7777 cells) and primary rat hepatocytes. Cells cultured for 3 days in the presence of UDCA, the BC lumen was enlarged and the bile canaliculi were surrounded by multiple cells (≥5) with a continuous canal-like structure, reminiscent of the in vivo BC network. The effects were dependent on p38MAPK and conventional PKC in McA-RH cells, and partially dependent on p38MAPK, MAPK/ERK kinase, and conventional PKC in primary rat hepatocytes. These findings were then studied in vivo in a rat model of dimethylnitrosamine-induced hepatic injury, in which the BC network is significantly disrupted. In accordance with the in vitro observations, administration of UDCA (40 mg/kg/day) to the injured rats for 18 days improved the BC network compared with the vehicle control. Serum hepatic markers were not altered by UDCA treatment, suggesting that the morphological effects were due to the direct actions of UDCA on network formation. Our data provide new evidence of the pharmacological potential of UDCA in accelerating or regenerating BC network formation in vitro, in hepatic cell culture models, and in vivo in a rat model of hepatic injury, and provide a basis for understanding its hepatoprotective effects.
authors: Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan.
authors: Yuki
authors: Y
authors: Ikebuchi
authors: Hidetoshi
authors: H
authors: Shimizu
authors: Kousei
authors: K
authors: Ito
authors: Takashi
authors: T
authors: Yoshikado
authors: Yoshihide
authors: Y
authors: Yamanashi
authors: Tappei
authors: T
authors: Takada
authors: Hiroshi
authors: H
authors: Suzuki
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000187:drug effects* / Q000254:growth & development; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000633:toxicity; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D013656:Taurocholic Acid; D014580:Ursodeoxycholic Acid; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases