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

Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):14-25. doi: 10.1016/j.bbadis.2018.10.010. Epub 2018 Oct 6.

Abstract

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.

Keywords: Antioxidant; Ceramide; Non-alcoholic fatty liver disease; Oxidative stress; Phosphatidylcholine; Vitamin E.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Ceramidase
  • Animals
  • Antioxidants / pharmacology
  • Cholesterol / metabolism
  • Diet, High-Fat
  • Dietary Supplements
  • Disease Models, Animal
  • Disease Progression
  • Fatty Liver / metabolism
  • Fibrosis / drug therapy
  • Inflammation / drug therapy
  • Insulin Resistance
  • Lipid Metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Obesity / metabolism
  • Oxidative Stress / drug effects
  • Phosphatidylethanolamine N-Methyltransferase / genetics
  • Phosphatidylethanolamine N-Methyltransferase / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor)
  • RNA, Messenger
  • Vitamin E / administration & dosage
  • Vitamin E / metabolism*
  • Vitamin E / pharmacology*

Substances

  • Antioxidants
  • RNA, Messenger
  • Vitamin E
  • Cholesterol
  • PEMT protein, mouse
  • Phosphatidylethanolamine N-Methyltransferase
  • Phosphotransferases (Alcohol Group Acceptor)
  • ceramide kinase
  • Acid Ceramidase
  • Asah1 protein, mouse