Adaptation to Choline Deprivation: Choline Redistribution and Choline Storage

Abstract

In mammals, the only endogenous pathway for choline biosynthesis is the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by PE N-methyltransferase (PEMT). Complete choline deprivation achieved by feeding Pemt−/− mice a choline-deficient (CD) diet is lethal due to liver failure. However, CD mice that lack both PEMT and multiple drug resistant protein 2 (MDR2) are resistant to liver failure and survive for at least 3 months. This allowed us to uncover several new adaptations to choline deprivation besides classical adaptations such as up-regulation of PEMT. The newly found adaptations to choline deprivation include choline recycling, maintenance of membrane integrity via maintenance of PC/PE ratio, and choline redistribution and choline storage that is the main focus of this presentation. Total choline-containing metabolites in the liver of CD-Mdr2−/−/Pemt−/− mice were maintained via down-regulation of choline oxidation suggesting that liver could obtain choline from extrahepatic sources. By in vivo injection of [3H]choline into CD-Mdr2−/−/Pemt−/− mice, we found the existence of choline redistribution from muscle to liver and brain. Although CD-Pemt−/− mice failed to adapt to choline deprivation, it was intriguing to explore whether or not these mice had adaptive response to choline deprivation. Interestingly, we found that female Pemt−/− mice showed one-day delay of liver damage as compared to male Pemt−/− mice when fed the CD diet. This allowed us to show that in response to choline deprivation, mice can mobilize extrahepatic PC to liver via enhancing HDL-PC efflux and the tissues for enhanced HDL-PC efflux are sites of choline storage. However, choline is stored and can be supplied, unlike fat and glycogen, in mice for only one day during choline deprivation. (Funded by CIHR)