title: Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7α-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis.
abstract: To examine the mRNA expression of hepatobiliary transporters in primary biliary cirrhosis (PBC) patients and to compare bile acid absorption, synthesis, and efflux in patients with non-end-stage and end-stage PBC, we obtained liver samples from PBC patients by percutaneous needle biopsy. End-stage PBC was defined as follows: histological stage IV; cirrhosis; serum total bilirubin, ≥4.0 mg/dl; and Child-Pugh Class C. The mRNA expression levels of sodium taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), and hepatic cholesterol 7α-hydroxylase (CYP7A1) were significantly higher in the PBC patients than in the controls (P < 0.01). The mRNA levels of NTCP and BSEP were significantly higher in the end-stage PBC patients than in the controls (P < 0.01). However, hepatic CYP7A1 mRNA expression decreased significantly (by 70%) in the patients with end-stage PBC as compared to the controls and the patients with non-end-stage PBC (P < 0.01). The hepatic expression of transporters mediating bile acid influx and efflux showed sustained elevation, whereas that of the rate-limiting enzyme for bile acid biosynthesis was attenuated in the end-stage PBC patients. Thus, mechanisms may be present preventing the accumulation of toxic bile acids in the hepatocytes of end-stage PBC patients.
authors.affiliation: Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. yaz@fukuoka-u.ac.jp
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Takeyama
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kanegae
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Inomata
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Takata
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Ueda
authors.forename: Keiji
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morihara
authors.forename: Shinya
authors.initials: S
authors.lastname: Nishizawa
authors.forename: Akira
authors.initials: A
authors.lastname: Anan
authors.forename: Makoto
authors.initials: M
authors.lastname: Irie
authors.forename: Kaoru
authors.initials: K
authors.lastname: Iwata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shakado
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sohda
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sakisaka
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D058625:End Stage Liver Disease / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; C071908:sodium-bile acid cotransporter; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase