Estrogen induces the PEMT (phosphatidylethanolamine N‐methyltransferase) gene in human and murine hepatocytes

Abstract

Choline is an essential nutrient for humans, though some part of this requirement can be met by endogenous synthesis catalyzed by phosphatidylethanolamine N‐methyltransferase (PEMT). Human diets which lack sufficient choline intake can result in organ and muscle dysfunction. Pre‐menopausal women are more resistant to choline deficiency than post‐menopausal women and men. There is evidence in animal models which suggests that estrogen can increase PEMT activity. The goal of this study is to investigate whether and how the PEMT gene is regulated by estrogen. Real Time RT‐PCR revealed gene transcription was increased in a dose‐dependent manner in cultured primary mouse hepatocytes treated with various concentrations of 17B‐estradiol for 24 hours. Protein levels and enzyme activity were also increased. The human PEMT promoter contains eight putative estrogen response elements (EREs) and an Electrophoretic Mobility Shift Assay (EMSA) revealed that a 41 bp segment, which contains two putative EREs (2 and 3), can bind estrogen receptor complexes. Transfection studies, in which the human PEMT promoter is linked to a promoterless luciferase reporter gene, will be used to determine whether estrogen regulates promoter activity. This work supported by NIH grants to SZ(DK55865, AG09525, DK56350).

NAFLD in normal weight individuals

“…Lower hepatic PEMT expression was also associated with lower BMI [80], in keeping with the demonstration that PEMT −/− mice are protected from high fat diet-induced obesity and insulin resistance [84,85]. Because the PEMT gene is regulated by estrogen [86,87], the detrimental impact of choline deficiency may be exacerbated following the menopausal transition, consistent with findings from choline depletion [73,88] and observational studies [75]. Together, findings from human and mouse studies suggest that choline deficiency, whether due to low PEMT expression or inadequate dietary intake, may be related to the development of NAFLD and a susceptibility toward progressive disease specifically in lean individuals.…”

“…For example, postmenopausal women had significantly worse fibrosis compared to premenopausal women, although both groups had similarly low levels of choline intake [75]. As noted above, reduced endogenous production of estrogen results in diminished PEMT expression, which may lead a greater susceptibility to the development of NAFLD in postmenopausal women with chronic states of choline deficiency [86,87].…”

Deficiency of the lipid flippase ATP10A causes diet-induced dyslipidemia in female mice

“…However, the liver employs an additional pathway catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT), which converts PE to PC using three methyl groups from S-adenosylmethionine 45 . Interestingly, PEMT activity exhibits sexual dimorphism 46 and the Pemt gene is regulated by estrogen 47 , 48 . Furthermore, Pemt −/− mice on a high-fat diet display sex-specific differences in their plasma lipoprotein profiles 49 .…”

Establishment of a new nonalcoholic steatohepatitis model; Ovariectomy exacerbates nonalcoholic steatohepatitis-like pathology in diabetic rats

“…An OVX-induced decrease in Pemt was observed in SDT-fatty rats, and a downward trend was also observed in other rat strains. In in vitro, mRNA expression and enzymatic activity of PEMT are upregulated by 17β-estradiol stimulation (Resseguie et al, 2007), and in vivo, NASH models lacking PEMT have been reported to have a worse condition compared to wild-type (Nakatsuka et al, 2016). In SDT-fatty rats, PL synthesis in the liver might be suppressed by the OVX-induced reduction of female hormone levels.…”