Mice heterozygous for the Mdr2 gene demonstrate decreased PEMT activity and diminished steatohepatitis on the MCD diet.
OBJECTIVE
The administration of a methionine and choline deficient (MCD) diet to mice serves as an animal model of NASH. The multidrug resistant 2 (Mdr2) P-glycoprotein encodes for the canalicular phospholipid transporter, and Mdr2 (+/-) mice secrete 40% less phosphatidylcholine than wild-type mice. We have hypothesized that phosphatidylethanolamine-N-methyl transferase (PEMT) up-regulation is a consequence of MCD diet administration, and is important for the pathogenesis of steatohepatitis in this model. However, the effect of decreased phosphatidylcholine secretion and modulation of PEMT on the development of diet-induced steatohepatitis in Mdr2 (+/-) mice has not been explored. Thus, the purpose of the study is to examine the effects of the MCD diet on Mdr2 (+/-) mice.


METHODS
Mdr2 (+/-) and Mdr2 (+/+) mice were treated with an MCD or control diet for up to 30 days, and the severity of steatohepatitis, PEMT activity and hepatic S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) levels were measured.


RESULTS
Serum ALT levels, hepatic inflammation, and PEMT activity were significantly lower, and hepatic SAM:SAH ratios were significantly higher in Mdr2 (+/-) mice at 7 and 30 days on the MCD diet.


CONCLUSIONS
Mdr2 (+/-) mice have diminished susceptibility to MCD diet-induced NASH, which is associated with a relative decrease in PEMT activity and increased SAM:SAH ratios.
Igolnikov
Alexander C
AC
Department of Medicine, Division of Hepatology, Feinberg School of Medicine, Northwestern University, Tarry 14-701,303 E. Chicago Ave., Chicago, IL 60611, USA.
Green
Richard M
RM
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002794:Choline / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006505:Hepatitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D008715:Methionine / Q000633:toxicity; D051379:Mice; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000378:metabolism*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D012720:Severity of Illness Index; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D015415:Biomarkers; D002794:Choline; D008715:Methionine; D050918:Phosphatidylethanolamine N-Methyltransferase; D012435:S-Adenosylhomocysteine; D012436:S-Adenosylmethionine; D000097202:ATP-Binding Cassette Sub-Family B Member 4