Role of hepatic phospholipids in development of liver injury in Mdr2 (Abcb4) knockout mice.

Abstract

BACKGROUND/AIMS:

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.

• Authors: Anna Baghdasaryan, Peter Fickert, Andrea Fuchsbichler, Dagmar Silbert, Judith Gumhold, Gerd Hörl, Cord Langner, Tarek Moustafa, Emina Halilbasic, Thierry Claudel, Michael Trauner
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 28 Issue 7 Pg. 948-58 (Aug 2008) ISSN: 1478-3231 [Electronic] United States
• PMID: 18410282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Lecithins
• Cholesterol
• Alkaline Phosphatase
• Bilirubin

Topics

• ATP Binding Cassette Transporter, Subfamily B (deficiency, genetics, metabolism)
• Alkaline Phosphatase (blood)
• Animals
• Bile (metabolism)
• Bilirubin (blood)
• Cell Proliferation (drug effects)
• Cholestasis, Intrahepatic (chemically induced, metabolism, pathology)
• Cholesterol (metabolism)
• Choline Deficiency (metabolism, pathology)
• Diet
• Disease Models, Animal
• Drug Resistance, Multiple
• Hepatocytes (drug effects, metabolism, pathology)
• Lecithins (administration & dosage, metabolism)
• Liver (drug effects, metabolism, pathology)
• Liver Function Tests
• Male
• Mice
• Mice, Knockout
• ATP-Binding Cassette Sub-Family B Member 4