Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat.
OBJECTIVE
Alterations in hepatobiliary transporters may render fatty livers more vulnerable against various toxic insults.


METHODS
We therefore studied expression and function of key organic anion transporters and their transactivators in 8-week-old obese Zucker rats, an established model for non-alcoholic fatty liver disease.


RESULTS
Compared to their heterozygous littermates, obese animals showed a significant reduction in canalicular bile salt secretion, which was paralleled by significantly diminished Oatp2 mRNA and protein levels together with reduced nuclear HNF3beta, while expression of bile salt export pump, organic anion transporter (Oatp) 1 and multidrug resistance-associated protein (Mrp) 4 were unchanged. Impaired bile salt-independent bile flow in obese rats was associated with a 50% reduction of biliary secretion of the Mrp 2 model-substrates glutathione disulfide and S-(2,4-dinitrophenyl)glutathione. In line Mrp2 protein expression was reduced by 50% in obese rats.


CONCLUSIONS
Oatp2 and Mrp2 expression is decreased in fatty liver and may impair metabolism and biliary secretion of numerous xenobiotics. Reduction of bile salt secretion and absence of biliary GSH excretion may contribute to impaired bile flow and posthepatic disorders associated with biliary GSH depletion.
Geier
Andreas
A
Department of Gastroenterology, Aachen University (RWTH), Aachen, Germany. ageier@ukaachen.de
Dietrich
Christoph G
CG
Grote
Tobias
T
Beuers
Ulrich
U
Prüfer
Thomas
T
Fraunberger
Peter
P
Matern
Siegfried
S
Gartung
Carsten
C
Gerbes
Alexander L
AL
Bilzer
Manfred
M
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D001646:Bile / Q000502:physiology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000096:biosynthesis*; D051381:Rats; D011924:Rats, Zucker
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D027361:Organic Anion Transporters; C503597:Slco1a4 protein, rat; D005978:Glutathione