P. Fickert et al., Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver, GASTROENTY, 121(1), 2001, pp. 170-183
Background & Aims: 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 U
DCA and cholic acid (CA) on the expression of hepatocellular transporters f
or bile acids (Ntcp, Bsep), organic anions (Oatp1, Mrp2), organic cations (
Mdr1a/b), and phospholipids (Mdr2) in mouse liver. Methods: Bile flow/compo
sition was analyzed in UDCA- or CA-fed mice. Transporter expression was stu
died by reverse-transcription polymerase chain reaction, Western blotting,
and immunofluorescence microscopy. Results: UDCA had no effect on basolater
al Ntcp and down-regulated Oatp1, whereas canalicular Bsep and Mrp2 were up
-regulated. CA down-regulated basolateral Ntcp and Oatp1, whereas canalicul
ar Bsep, Mrp2, and Mdr1a/b were up-regulated. Neither UDCA nor CA affected
Mdr2 expression. Both UDCA and CA stimulated biliary bile acid and glutathi
one excretion, although only CA increased phospholipid and cholesterol excr
etion. Conclusions: Down-regulation of basolateral and up-regulation of can
alicular transporters in response to CA may represent a defense mechanism,
in an attempt to prevent hepatocellular accumulation of potentially toxic b
ile acids. The therapeutic effects of UDCA may be caused in part by stimula
tion of canalicular transporter expression in the absence of hepatocellular
toxicity.