Role of hepatic phospholipids in development of liver injury in Mdr2 (Abcb4) knockout mice.
OBJECTIVE
Multidrug resistance protein 2 (Abcb4) gene knockout mice (Mdr2(-/-)) lack phosphatidylcholine (PC) excretion into bile and spontaneously develop sclerosing cholangitis, biliary fibrosis and hepatocellular carcinomas. We therefore aimed to test whether formation and hepatic retention of abnormal PC metabolites contribute to the pathogenesis of liver injury in Mdr2(-/-) mice.


METHODS
Mdr2(-/-) mice were either fed a diet supplemented with soybean lecithin 2.5% w/w [phosphatidylcholine-enriched diet (PCD), to increase hepatic PC content] or a choline-deficient diet (CDD, to reduce hepatic PC content) for 4 weeks; controls received chow with energy and nutrient content equivalent to PCD and CDD. Serum liver tests, liver histology, markers of fibrosis, cholangiocyte activation, cell proliferation and thin-layer chromatography for phospholipid (PL) composition were carried out.


RESULTS
PCD decreased serum alkaline phosphatase and total bilirubin levels compared with controls, while liver histology as well as hepatic hydroxyproline content as markers of liver fibrosis did not differ among groups. Both PCD and CDD decreased hepatocellular proliferation compared with controls. Hepatic, serum and biliary PLs remained unchanged despite dietary manipulations and no potentially toxic PL metabolites were detected.


CONCLUSIONS
Mdr2(-/-) mice maintain stable hepatic, serum and biliary PL metabolism in response to dietary PC manipulations. Our findings therefore suggest that liver injury in Mdr2(-/-) mice is not due to formation of toxic PL metabolites.
Baghdasaryan
Anna
A
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Laboratory of Experimental and Molecular Hepatology, Medical University, Graz, Austria.
Fickert
Peter
P
Fuchsbichler
Andrea
A
Silbert
Dagmar
D
Gumhold
Judith
J
Hörl
Gerd
G
Langner
Cord
C
Moustafa
Tarek
T
Halilbasic
Emina
E
Claudel
Thierry
T
Trauner
Michael
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D002796:Choline Deficiency / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054709:Lecithins / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000469:Alkaline Phosphatase; D001663:Bilirubin; D002784:Cholesterol; D054709:Lecithins; D000097202:ATP-Binding Cassette Sub-Family B Member 4