BACKGROUND AND 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 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.
BACKGROUND AND 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 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.
Authors: Peter Fickert; Michael Trauner; Andrea Fuchsbichler; Conny Stumptner; Kurt Zatloukal; Helmut Denk Journal: Am J Pathol Date: 2002-12 Impact factor: 4.307
Authors: Anna Baghdasaryan; Thierry Claudel; Astrid Kosters; Judith Gumhold; Dagmar Silbert; Andrea Thüringer; Katharina Leski; Peter Fickert; Saul J Karpen; Michael Trauner Journal: Gut Date: 2010-04 Impact factor: 23.059
Authors: Peter Fickert; Andrea Fuchsbichler; Hanns-Ulrich Marschall; Martin Wagner; Gernot Zollner; Robert Krause; Kurt Zatloukal; Hartmut Jaeschke; Helmut Denk; Michael Trauner Journal: Am J Pathol Date: 2006-02 Impact factor: 4.307