The role of bile salt composition in liver pathology of mdr2 (-/-) mice: differences between males and females.
OBJECTIVE
The mouse mdr2 gene encodes a P-glycoprotein expressed in the canalicular membrane of the hepatocyte. Mice in which this gene has been inactivated (mdr2 -/-) show a defect in biliary phospholipid and cholesterol secretion and develop non-suppurative cholangitis. We hypothesized that secretion of bile salts without lipids initiates this liver disease.


METHODS
To delineate the pathologic process, mdr2 (-/-) mice were fed different bile salt-supplemented diets for 22 weeks after weaning. Aspects of liver pathology including eosinophilic bodies, portal inflammation, ductular proliferation, mitotic activity and fibrosis were semi-quantitatively scored.


RESULTS
It was observed that liver pathology was more severe in female than in male mice when fed a purified control diet. This correlated with a more hydrophobic bile salt composition of female vs. male bile. When increasing amounts of cholate were added to the diet (0.01% and 0.1%), the secretion of taurocholate increased and this was accompanied by a more severe liver pathology. At the high dose of cholate (0.1%), the bile salt compositions of male and female mice became similar, as did the severity of the histological score. Addition of cholate to the diet did not induce liver pathology in (+/+) mice. Addition of ursodeoxycholate to the diet (0.5%) led to a near complete replacement of biliary bile salts by tauroursodeoxycholate and this reduced pathology and dissipated the difference between males and females.


CONCLUSIONS
These observations support our hypothesis that liver pathology in the mdr2 (-/-) mouse is caused by bile salts and depends on the hydrophobicity c.q. cytotoxicity of biliary bile salts.
van Nieuwerk
C M
CM
Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
Groen
A K
AK
Ottenhoff
R
R
van Wijland
M
M
van den Bergh Weerman
M A
MA
Tytgat
G N
GN
Offerhaus
J J
JJ
Oude Elferink
R P
RP
D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D004032:Diet; D005260:Female; D019450:Genes, MDR; D008107:Liver Diseases / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012727:Sex Characteristics; D012995:Solubility; D013655:Taurochenodeoxycholic Acid / Q000502:physiology; D014580:Ursodeoxycholic Acid / Q000502:physiology; D014867:Water / Q000737:chemistry
D001647:Bile Acids and Salts; D014867:Water; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D014580:Ursodeoxycholic Acid