Lack of phosphatidylethanolamine N-methyltransferase alters hepatic phospholipid composition and induces endoplasmic reticulum stress

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Gao, Xia¹  van der Veen, Jelske N.¹  Vance, Jean E.²  Thiesen, Aducio³  Vance, Dennis E.¹  Jacobs, Rene L.⁴ 

[1] Univ Alberta, Dept Biochem, Edmonton, AB T6G 2E1, Canada

[2] Univ Alberta, Dept Med, Edmonton, AB T6G 2E1, Canada

[3] Univ Alberta, Div Anat Pathol, Edmonton, AB T6G 2E1, Canada

[4] Univ Alberta, Dept Agr Food & Nutr Sci, Edmonton, AB T6G 2E1, Canada

关键词: Steatohepatitis;    Unfolded protein response;    Phenylbutyric acid;    Phosphatidylcholine;    Phosphatidylethanolamine;    ER stress;   

DOI  :  10.1016/j.bbadis.2015.09.006

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier B.V. All rights reserved.

【 授权许可】

Free