Biochemical and Evolutionary Significance of Phospholipid Methylation

Abstract

All nucleated mammalian cells synthesize phosphatidylcholine from choline via the CDP-choline pathway. Hepatocytes have a second pathway for the synthesis of phosphatidylcholine, a stepwise methylation of phosphatidylethanolamine, catalyzed by phosphatidylethanolamine N-methyltransferase and encoded by the Pempt gene. We report that when Pempt-deficient mice were fed a choline-deficient diet for 3 days, severe liver pathology occurred apparently due to a lack of phosphatidylcholine biosynthesis. The hepatic concentration of phosphatidylcholine decreased by 50% compared with wild type mice on the diet. The levels of plasma triacylglycerols and cholesterol were decreased by greater than 90% in the Pempt-deficient mice. We suggest that the Pempt gene has been maintained during evolution to provide phosphatidylcholine when dietary choline is insufficient, as might occur during starvation or pregnancy.

The unique acyl chain specificity of biliary phosphatidylcholines in mice is independent of their biosynthetic origin in the liver

“…Surprisingly, neither the CDPcholine mice (i.e., Pempt Ϫ/Ϫ mice fed the CS diet), nor PEMT mice (i.e., Pempt ϩ/ϩ mice fed the CD diet) showed any overt signs of abnormality, suggesting that inactivation of either of the 2 pathways can be compensated for, at least partially, by the remaining pathway. 4 Nevertheless, in the present study, we identified a liver-specific function, namely the supply of physiological amounts of PC to bile, that cannot be fully compensated for by the PEMT pathway. Although the results clearly illustrate that each of the 2 PC biosynthetic pathways can provide PC for secretion into the bile, the reduced concentration of PC and especially the reduced PC-to-bile acid ratio in gallbladder bile of PEMT mice indicates that, under physiological conditions, the CDP-choline pathway contributes a greater proportion of PC to bile than the PEMT pathway.…”

“…Another potential benefit of the PEMT pathway involves its ability to guarantee choline homeostasis, via subsequent catabolism of PE-derived PC, in instances of nutritional choline insufficiency. 4 The contribution of the 2 biosynthetic pathways for bile PC formation has not been clearly resolved, because it was previously not possible to consider each of the 2 PC biosynthetic pathways separately and independently. Available data from past studies do suggest that PC from the CDP-choline pathway, as well as PC originating from PE-methylation, are secreted into bile.…”

“…2,3 In mice, the total amount of PC secreted by the liver into the bile in a single day is equivalent to the amount of PC present in the liver. 4 Studies using targeted gene disruption technology demonstrated that the product of the mdr2 gene is essential for biliary PC secretion in mice. 5 It is now firmly established that the mdr2 gene encodes a protein that facilitates the translocation of PC from the inner to the outer leaflet of the canalicular membrane.…”

Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction

“…We developed quantitative real-time PCR assays to critically evaluate the relative contributions of the different CCTs to PtdCho production in mouse tissues. The PEMT transcripts were also quantified because this enzyme, in addition to the CCTs, mediates a reaction significant for PtdCho biosynthesis in liver tissue (54). This technique has a linear range of more than 4 orders of magnitude which allows for wide-ranging detection of both high and very low copy number transcripts in a sample, and the probe designs are based on a common hybridization condition optimized for all the transcripts.…”

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

“…The monomeric CHK proteins combine to form the homo-or hetero-dimeric active forms (15) that catalyze the phosphorylation of choline to phosphocholine in the first committed step in the Kennedy pathway (the cytidine diphosphate (CDP)-choline pathway) for the biosynthesis of phosphatidylcholine (PC) (16). PC is the major phospholipid component of the eukaryotic plasma membrane external leaflet (17), an important precursor for many signaling molecules (18), and is thought to be essential for mammalian survival (19,20). The immediate biosynthetic product of CHK, phosphocholine, may also be an important secondary messenger in regulating cell growth signaling and proliferation (21).…”