title: Lack of phosphatidylethanolamine N-methyltransferase alters hepatic phospholipid composition and induces endoplasmic reticulum stress.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress is associated with development of steatohepatitis. Phosphatidylethanolamine N-methyltransferase (PEMT) is a hepatic enzyme located on the ER and mitochondria-associated membranes and catalyzes phosphatidylcholine (PC) synthesis via methylation of phosphatidylethanolamine (PE). We hypothesized that PEMT deficiency in mice alters ER phospholipid content, thereby inducing ER stress and sensitizing the mice to diet-induced steatohepatitis.
  
  
  METHODS
  PC and PE mass were measured in hepatic ER fractions from chow-fed and high fat-fed Pemt(-/-) and Pemt(+/+) mice. Proteins implicated in ER stress and the unfolded protein response (UPR) were assessed in mouse livers and in McArdle-RH7777 hepatoma cells that expressed or lacked PEMT. The chemical chaperone 4-phenyl butyric acid was administered to cells and HF-fed Pemt(-/-) mice to alleviate ER stress.
  
  
  RESULTS
  In chow-fed Pemt(-/-) mice, the hepatic PC/PE ratio in the ER was lower than in Pemt(+/+) mice, and levels of ER stress markers, CHOP and BIP, were higher without activation of the UPR. In livers of HF-fed Pemt(-/-) mice the ER had a lower PC/PE ratio, and exhibited more ER stress and UPR activation. Similarly, the UPR was repressed in McArdle cells expressing PEMT compared with those lacking PEMT, with concomitantly lower levels of CHOP and BIP. 4-Phenyl butyric acid attenuated activation of the UPR and ER stress in McArdle cells lacking PEMT, but not the hepatic ER stress in HF-fed Pemt(-/-) mice.
  
  
  CONCLUSIONS
  PEMT deficiency reduces the PC/PE ratio in the ER and induces ER stress, which sensitizes the mice to HF-induced steatohepatitis.
authors.affiliation: Group on Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Group on Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jelske N
authors.initials: JN
authors.lastname: van der Veen
authors.affiliation: Group on Molecular and Cell Biology of Lipids, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
authors.affiliation: Division of Anatomical Pathology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Aducio
authors.initials: A
authors.lastname: Thiesen
authors.affiliation: Group on Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
authors.affiliation: Group on Molecular and Cell Biology of Lipids, Canada; Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, AB, Canada. Electronic address: rjacobs@ualberta.ca.
authors.forename: René L
authors.initials: RL
authors.lastname: Jacobs
keywords: ER stress; Phenylbutyric acid; Phosphatidylcholine; Phosphatidylethanolamine; Steatohepatitis; Unfolded protein response