Hepatic PEMT Expression Decreases with Increasing NAFLD Severity

Choline deficiency causes hepatic fat accumulation, and is associated with a higher risk of nonalcoholic fatty liver disease (NAFLD) and more advanced NAFLD-related hepatic fibrosis. Reduced expression of hepatic phosphatidylethanolamine N-methyltransferase (PEMT), which catalyzes the production of phosphatidylcholine, causes steatosis, inflammation, and fibrosis in mice. In humans, common PEMT variants impair phosphatidylcholine synthesis, and are associated with NAFLD risk. We investigated hepatic PEMT expression in a large cohort of patients representing the spectrum of NAFLD, and examined the relationship between PEMT genetic variants and gene expression. Hepatic PEMT expression was reduced in NAFLD patients with inflammation and fibrosis (i.e., nonalcoholic steatohepatitis or NASH) compared to participants with normal liver histology (beta = -1.497; p = 0.005). PEMT levels also declined with increasing severity of fibrosis with cirrhosis < incomplete cirrhosis < bridging fibrosis (beta = -1.185; p = 0.011). Hepatic PEMT expression was reduced in postmenopausal women with NASH compared to those with normal liver histology (beta = -3.698; p = 0.030). We detected a suggestive association between rs7946 and hepatic fibrosis (p = 0.083). Although none of the tested variants were associated with hepatic PEMT expression, computational fine mapping analysis indicated that rs4646385 may impact PEMT levels in the liver. Hepatic PEMT expression decreases with increasing severity of NAFLD in obese individuals and postmenopausal women, and may contribute to disease pathogenesis in a subset of NASH patients.

Automated summary

Choline deficiency is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD) and more advanced NAFLD-related hepatic fibrosis. Reduced expression of the hepatic phosphatidylethanolamine N-methyltransferase (PEMT) enzyme causes steatosis, inflammation, and fibrosis in mice, and common PEMT variants in humans impair phosphatidylcholine synthesis and increase NAFLD risk. This study investigated the expression of hepatic PEMT and its genetic variants in a large cohort of NAFLD patients and found that reduced PEMT expression is linked to inflammation and fibrosis in NAFLD patients, with severity of fibrosis being a factor. Additionally, reduced PEMT expression was observed in postmenopausal women with NAFLD, and certain genetic variants were suggestive of an association with hepatic fibrosis.