Vitamin E alleviates non-alcoholic fatty liver disease in phosphatidylethanolamine N-methyltransferase deficient mice

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2019-01, Vol.1865 (1), p.14-25
• Main Authors: Presa, Natalia, Clugston, Robin D., Lingrell, Susanne, Kelly, Samuel E., Merrill, Alfred H., Jana, Sayantan, Kassiri, Zamaneh, Gómez-Muñoz, Antonio, Vance, Dennis E., Jacobs, Rene L., van der Veen, Jelske N.
• Format: Article
• Language: English
• Subjects: Antioxidant; Ceramide; Non-alcoholic fatty liver disease; Oxidative stress; Phosphatidylcholine; Vitamin E
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2018.10.010

Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC), mainly in the liver. Pemt−/− mice are protected from high-fat diet (HFD)-induced obesity and insulin resistance, but develop severe non-alcoholic fatty liver disease (NAFLD) when fed a HFD, mostly due to impaired VLDL secretion. Oxidative stress is thought to be an essential factor in the progression from simple steatosis to steatohepatitis. Vitamin E is an antioxidant that has been clinically used to improve NAFLD pathology. Our aim was to determine whether supplementation of the diet with vitamin E could attenuate HFD-induced hepatic steatosis and its progression to NASH in Pemt−/− mice. Treatment with vitamin E (0.5 g/kg) for 3 weeks improved VLDL-TG secretion and normalized cholesterol metabolism, but failed to reduce hepatic TG content. Moreover, vitamin E treatment was able to reduce hepatic oxidative stress, inflammation and fibrosis. We also observed abnormal ceramide metabolism in Pemt−/− mice fed a HFD, with elevation of ceramides and other sphingolipids and higher expression of mRNAs for acid ceramidase (Asah1) and ceramide kinase (Cerk). Interestingly, vitamin E supplementation restored Asah1 and Cerk mRNA and sphingolipid levels. Together this study shows that vitamin E treatment efficiently prevented the progression from simple steatosis to steatohepatitis in mice lacking PEMT. •Vitamin E prevents the development of steatohepatitis in Pemt−/− mice.•Oxidative stress contributes to the development of steatohepatitis in Pemt−/− mice.•Excessive accumulation of ceramides in livers of Pemt−/− mice fed a high-fat diet•Vitamin E does not reduce hepatic triacylglycerol accumulation in Pemt−/− mice.•Oxidative stress, ER stress and ceramide accumulation prevented by vitamin E