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.
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.
Takeyama
Yasuaki
Y
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
Kanegae
Kazuko
K
Inomata
Shinjiro
S
Takata
Kazuhide
K
Tanaka
Takashi
T
Ueda
Shu-Ichi
S
Yokoyama
Keiji
K
Morihara
Daisuke
D
Nishizawa
Shinya
S
Anan
Akira
A
Irie
Makoto
M
Iwata
Kaoru
K
Shakado
Satoshi
S
Sohda
Tetsuro
T
Sakisaka
Shotaro
S
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
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