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

• PEMT deficiency reduces the molar ratio of PC:PE in the ER and leads to hepatic ER stress independent of hepatic TG.
• Expression of PEMT in McArdle-RH7777 hepatoma cells reverses ER stress caused by lack of PEMT.
• Hepatic ER stress induced by PEMT deficiency sensitizes the liver to HF-induced steatohepatitis in Pemt−/− mice.
• The chemical chaperone 4-phenylbutyric acid only slightly alleviates steatosis and ER stress in HF-fed Pemt−/− mice.

Background & aimsEndoplasmic 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.MethodsPC 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.ResultsIn 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.ConclusionPEMT deficiency reduces the PC/PE ratio in the ER and induces ER stress, which sensitizes the mice to HF-induced steatohepatitis.