Liver and neuronal changes in PEMT knockout mice.

摘要

This dissertation reports the role of phosphatidylethanolamine N-methyltransferase (PEMT) which is encoded by the pemt gene on liver function and fetal brain development. After a general review of choline metabolism, PEMT pathway and brain development, major findings based on animal studies are presented into three papers. The first paper reports that pemt knockout mice have depleted choline and choline metabolites in their livers and have severe hepatic steatosis despite an adequate intake of dietary choline. These findings indicate that the PEMT pathway plays an indispensable role in maintaining normal choline pools and also suggested that the pemt knockout model could be used as a choline deficient model in future studies. After analyzing the choline metabolite changes in the adult mice, we tested the hypothesis that the brain development would be affected in the PEMT knockout offspring in the second paper. Because our laboratory found that choline deficiency during late pregnancy altered neuronal cells' mitosis, differentiation, migration and apoptosis in the hippocampus, and that this led to memory function changes, we anticipated that PEMT knockout fetal brain would have similar changes.; However, in contrast to our expectation, fetal brains from the knockout animals had higher levels of brain development markers, which rendered them more like the choline supplemented rather than choline deficient animals. Further analysis of the S-adenosylmethionine (AdoMet) concentration revealed that these knockout animals had significant accumulation of AdoMet. Thus, hypermethylation could be one of the many reasons accounting for the observed changes. Since exploring all the possible mechanisms through the traditional biochemistry methods would be time-consuming, gene microarray techniques and knowledge of bioinformatics were employed in the third paper to screen for genes that changed significantly. These results were analyzed in the context of metabolic pathways and interpreted according to their biological functions.