Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamineN-methyltransferase.
Mice lacking phosphatidylethanolamineN-methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treatedPemt-/-mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation inPemt-/-livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD inPemt-/-mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treatedPemt-/-mice were similar to those inPemt+/+mice. Importantly,Pemt-/-mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis inPemt-/-mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT.
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Jelske N
JN
van der Veen
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Susanne
S
Lingrell
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Xia
X
Gao
Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Abhijit
A
Takawale
Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Zamaneh
Z
Kassiri
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Dennis E
DE
Vance
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada. Electronic address: rjacobs@ualberta.ca.
René L
RL
Jacobs
D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000069438:Ezetimibe / Q000008:administration & dosage; D011345:Fenofibrate / Q000008:administration & dosage*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase; D000069438:Ezetimibe; D011345:Fenofibrate
fibric acids; liver fibrosis; nonalcoholic fatty liver disease; peroxisome proliferator-activated receptor-α; phosphatidylcholine; steatohepatitis