Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline

Abstract

Choline is an essential nutrient for humans and is derived from the diet as well as from de novo synthesis involving methylation of phosphatidylethanolamine catalysed by the enzyme phosphatidylethanolamine N -methyltransferase (PEMT). This is the only known pathway that produces new choline molecules. We used mice with a disrupted Pemt-2 gene (which encodes PEMT; Pemt (-/-)) that have previously been shown to possess no hepatic PEMT enzyme. Male, female and pregnant Pemt (-/-) and wild-type mice ( n =5-6 per diet group) were fed diets of different choline content (deficient, control, and supplemented). Livers were collected and analysed for choline metabolites, steatosis, and apoptotic [terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling (TUNEL)] positive cells. We found that, in livers of Pemt (-/-) mice fed any of the diets, there was hepatic steatosis and significantly higher occurrence of TUNEL positive cells compared with wild-type controls. In male, female and pregnant mice, liver phosphatidylcholine concentrations were significantly decreased in Pemt (-/-) choline deficient and in Pemt (-/-) choline control groups but returned to normal in Pemt (-/-) choline supplemented groups. Phosphocholine concentrations in liver were significantly diminished in knockout mice even when choline was supplemented to above dietary requirements. These results show that PEMT normally supplies a significant portion of the daily choline requirement in the mouse and, when this pathway is knocked out, mice are unable to attain normal concentrations of all choline metabolites even with a supplemental source of dietary choline.

Choline: Critical Role During Fetal Development and Dietary Requirements in Adults

“…The PEMT pathway is not just a minor pathway that backs up the cytidine diphosphocholine pathway for phosphatidylcholine biosynthesis. Pemt−/− mice have lower choline pools in liver despite being fed sufficient or supplemental amounts of dietary choline (166), suggesting that choline production by PEMT is a significant source of choline relative to dietary intake. When PEMT is deleted in mice, plasma homocysteine concentrations fall by 50%, and when it is overexpressed, plasma homocysteine concentrations increase by 40% (58,115), demonstrating that PEMT activity is a major consumer of S-adenosylmethionine (and thereby a producer of homocysteine).…”

The Use of Selected Nutrition Supplements and Complementary and Alternative Medicine in Liver Disease

“…118 Thus, increased SAH levels and hypomethylation could critically influence pathways ranging from fat accumulation in the liver (eg, PEMT, which is critically involved in very low density lipoprotein [VLDL] production) to caspase-8 expression/activity, which could play a role in enhanced apoptosis of in many forms of liver injury such as ALD. 118,125,131 Thus, betaine therapy in theory could both decrease fatty infiltration in the liver, as well as decrease hepatocyte death.…”

Small molecule activators of pre-mRNA 3′ cleavage

“…Phosphocholine is a biosynthetic intermediate and breakdown product of phosphatidylcholine, an important membrane phosphospholipid. Its intracellular concentration is z1.1 mM (Choy et al 1978;Zhu et al 2003), and rises to z3 mM in cancer cells (Glunde et al 2004). These values are below the threshold for cleavage activation in our in vitro assay.…”