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The Murine Choline-Deficient, Ethionine-Supplemented (CDE) Diet Model of Chronic Liver Injury
Published on: October 21, 2017
Phosphatidylcholine homeostasis and liver failure
Zhaoyu Li1, Luis B Agellon, Dennis E Vance
1Department of Biochemistry, University of Alberta, Edmonton, Canada.
The Journal of Biological Chemistry
|September 8, 2005
Summary
Mice lacking both PEMT and MDR2 survived severe choline deprivation. This indicates that rapid depletion of hepatic phosphatidylcholine (PC) via biliary secretion, not PC reduction itself, causes lethality in choline-deficient mice.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Mammalian choline biosynthesis primarily occurs via phosphatidylethanolamine N-methyltransferase (PEMT).
- Complete choline deprivation is lethal in mice due to a 50% decrease in hepatic phosphatidylcholine (PC).
- PC is secreted into bile by the flippase, multiple drug-resistant protein 2 (MDR2).
Purpose of the Study:
- To investigate the role of biliary PC secretion in choline deprivation lethality.
- To determine if mice lacking both PEMT and MDR2 can survive choline deficiency.
Main Methods:
- Generation of Mdr2(-/-)/Pemt(-/-) double knockout mice.
- Feeding mice a choline-deficient (CD) diet.
- Analysis of hepatic PC levels, enzyme activities, and gene expression.
Main Results:
- Mdr2(-/-)/Pemt(-/-) mice survived >90 days on a CD diet, unlike Pemt(-/-) mice.
- Hepatic PC decreased by 50% in Mdr2(-/-)/Pemt(-/-) mice, similar to Pemt(-/-) mice.
- Survival was linked to choline recycling adaptations, including induced phospholipase A2, choline kinase, and CTP:phosphocholine cytidylyltransferase, and decreased choline oxidase.
Conclusions:
- Acute lethality in choline-deprived Pemt(-/-) mice is caused by rapid hepatic PC depletion via biliary secretion.
- Mice can adapt to severe choline deprivation through enhanced choline recycling pathways.
- MDR2-mediated biliary PC secretion is a critical factor in choline homeostasis and survival under choline deficiency.
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