Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver.
OBJECTIVE
Cholestasis is associated with retention of potentially toxic bile acids and alterations in hepatocellular transporter expression. Conversely, nontoxic ursodeoxycholic acid (UDCA) stimulates bile secretion and counteracts cholestasis. This study aimed to determine the effects of UDCA and cholic acid (CA) on the expression of hepatocellular transporters for bile acids (Ntcp, Bsep), organic anions (Oatp1, Mrp2), organic cations (Mdr1a/b), and phospholipids (Mdr2) in mouse liver.


METHODS
Bile flow/composition was analyzed in UDCA- or CA-fed mice. Transporter expression was studied by reverse-transcription polymerase chain reaction, Western blotting, and immunofluorescence microscopy.


RESULTS
UDCA had no effect on basolateral Ntcp and down-regulated Oatp1, whereas canalicular Bsep and Mrp2 were up-regulated. CA down-regulated basolateral Ntcp and Oatp1, whereas canalicular Bsep, Mrp2, and Mdr1a/b were up-regulated. Neither UDCA nor CA affected Mdr2 expression. Both UDCA and CA stimulated biliary bile acid and glutathione excretion, although only CA increased phospholipid and cholesterol excretion.


CONCLUSIONS
Down-regulation of basolateral and up-regulation of canalicular transporters in response to CA may represent a defense mechanism, in an attempt to prevent hepatocellular accumulation of potentially toxic bile acids. The therapeutic effects of UDCA may be caused in part by stimulation of canalicular transporter expression in the absence of hepatocellular toxicity.
Fickert
P
P
Department of Medicine, Karl-Franzens University, Auenbruggerplatz 15, A-8036 Graz, Austria.
Zollner
G
G
Fuchsbichler
A
A
Stumptner
C
C
Pojer
C
C
Zenz
R
R
Lammert
F
F
Stieger
B
B
Meier
P J
PJ
Zatloukal
K
K
Denk
H
H
Trauner
M
M
D000284:Administration, Oral; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D019826:Cholic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D001647:Bile Acids and Salts; D014580:Ursodeoxycholic Acid; D019826:Cholic Acid