Gao X.,Group on Molecular and Cell Biology of Lipids |
Gao X.,University of Alberta |
van der Veen J.N.,Group on Molecular and Cell Biology of Lipids |
van der Veen J.N.,University of Alberta |
And 7 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2015
Background & aims: 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. Conclusion: PEMT deficiency reduces the PC/PE ratio in the ER and induces ER stress, which sensitizes the mice to HF-induced steatohepatitis. © 2015 Elsevier B.V.