Sustained repression and translocation of Ntcp and expression of Mrp4 for cholestasis after rat 90% partial hepatectomy

• Published in: Journal of hepatology Vol. 55; no. 2; pp. 407 - 414
• Main Authors: Miura, Takuya, Kimura, Norihisa, Yamada, Toshiyuki, Shimizu, Takeshi, Nanashima, Naoki, Yamana, Daisuke, Hakamada, Kenichi, Tsuchida, Shigeki
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.08.2011; Elsevier
• Subjects: Animals; ATP Binding Cassette Subfamily B Member 11; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Bile acids; Bile Acids and Salts - blood; Biological and medical sciences; Biological Transport, Active; Bsep; Cholestasis; Cholestasis - etiology; Cholestasis - genetics; Cholestasis - metabolism; Cholestasis - pathology; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatectomy - adverse effects; Liver regeneration; Liver Regeneration - genetics; Liver Regeneration - physiology; Liver, biliary tract, pancreas, portal circulation, spleen; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mrp; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Ntcp; Organic Anion Transporters, Sodium-Dependent - genetics; Organic Anion Transporters, Sodium-Dependent - metabolism; Other diseases. Semiology; Rat hepatectomy; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; Symporters - genetics; Symporters - metabolism; Time Factors; Transcriptome; Translocation; Translocation; Bsep; Bile acids; Pcna; Oatp1; organic solute transporter; real-time polymerase chain reaction; Mrp; cytochrome P450; sodium-independent organic anion transporting polypeptides; Rat hepatectomy; proliferating cell nuclear antigen; Ost; multidrug resistance protein; Ntcp; RT-PCR; bile salt export pump; sodium-dependent taurocholate cotransporting polypeptide; Cyp; Cholestasis; Liver regeneration; Rat; Rodentia; Biliary tract disease; Hepatectomy; Vertebrata; Bile acids: Cholestasis; Mammalia; Treatment; Partial; Surgery; Bile acid; Animal; Cholostasis; Gastroenterology; Digestive diseases
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2010.11.023

Background & Aims To clarify the mechanism of persistent cholestasis after massive hepatectomy, the relationship between such cholestasis and the expression and localization of organic anion transporters for bile acids was examined in a rat model. Methods Male Sprague–Dawley rats were subjected to 90% hepatectomy, and tissues were harvested at 0, 1, 3, and 7 days for microarray analysis, quantitative real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry to examine the expression of multidrug resistance protein 4 (Mrp4), bile salt export pump (Bsep), and sodium-dependent taurocholate cotransporting polypeptide (Ntcp). Results Persistently elevated levels of serum bile acids were observed at days 3 and 7. RT-PCR and Western blotting indicated that the expression of Mrp4, a bile acid export pump located in the basolateral membrane, was increased at day 3. The expression of Ntcp, a transporter used to uptake bile acids from the sinusoids, was significantly decreased throughout the period. The levels of Bsep, an export pump localized to the canalicular membrane, were unchanged. Immunohistochemistry revealed the localization of Mrp4 and Bsep in the basolateral and canalicular membranes, respectively. On the other hand, at days 3 and 7, Ntcp was localized in the cytoplasm and was hardly detected in the basolateral membrane. Conclusions These results suggested that the sustained repression and translocation of Ntcp and the expression of Mrp4 at the basolateral membrane seem to be responsible for the high blood bile acids levels after massive hepatectomy.