Washington University in St. Louis

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Metabolomics to elucidate novel biochemical mechanisms of disease
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Hepatic Monoacylglycerol Acyltransferase 1 is Induce by Prolonged Food Deprivation to Modulate the Hepatic Fasting Response

Lutkewitte AJ, McCommis KS, Schweitzer GG, Chambers KT, Graham MJ, Wang L, Patti GJ, Hall AM, and Finck BN
Hepatic Monoacylglycerol Acyltransferase 1 is Induce by Prolonged Food Deprivation to Modulate the Hepatic Fasting Response
Journal of Lipid Research, 60, 528-538, 2019
doi:10.1194/jlr.M089722

During prolonged fasting, the liver plays a central role in maintaining systemic energy homeostasis by producing glucose and ketones in processes fueled by oxidation of fatty acids liberated from adipose tissue. In mice, this is accompanied by transient hepatic accumulation of glycerolipids. We found that the hepatic expression of monoacylglycerol acyltransferase 1 (Mogat1), an enzyme with monoacylglycerol acyltransferase (MGAT) activity that produces diacylglycerol from monoacylglycerol, was significantly increased in liver of fasted mice compared to mice given ad libitum access to food. Basal and fasting-induced expression of Mogat1 was markedly diminished in liver of mice lacking the transcription factor peroxisome proliferator-activated receptor α (PPARα). Suppressing Mogat1 expression in liver and adipose tissue with antisense oligonucleotides (ASO) reduced hepatic MGAT activity and triglyceride content compared to fasted controls. Surprisingly, the expression of many other PPARα target genes and PPARα activity was also decreased in mice given Mogat1 ASO. When mice treated with control or Mogat1 ASO were gavaged with the PPARα ligand, WY-14643, and then fasted for 18 h, WY-14643 administration reversed the effects of Mogat1 ASO on PPARα target gene expression and liver triglyceride content. In conclusion, Mogat1 is a fasting-induced PPARα target gene that may feed forward to regulate liver PPARα activity during food deprivation.

Washington University, Departments of Chemistry, Genetics, and Medicine. Saint Louis, Missouri 63110 USA