Hepatic monoacylglycerol acyltransferase 1 is induced by prolonged food deprivation to modulate the hepatic fasting response

Andrew J Lutkewitte,Kyle S Mccommis,George G Schweitzer,Kari T Chambers,Mark J Graham,Lingjue Wang,Gary J Patti,Angela M Hall,Brian N Finck

doi:10.1194/jlr.m089722

Abstract

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 diacyl-glycerol from monoacylglycerol, was significantly increased in the liver of fasted mice compared with mice given ad libitum access to food. Basal and fasting-induced expression of Mogat1 was markedly diminished in the liver of mice lacking the transcription factor PPARα. Suppressing Mogat1 expression in liver and adipose tissue with antisense oligonucleotides (ASOs) reduced hepatic MGAT activity and triglyceride content compared with fasted controls. Surprisingly, the expression of many other PPARα target genes and PPARα activity was also decreased in mice given Mogat1 ASOs. When mice treated with control or Mogat1 ASOs were gavaged with the PPARα ligand, WY-14643, and then fasted for 18 h, WY-14643 administration reversed the effects of Mogat1 ASOs 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.

Highlights

During prolonged fasting, the liver plays a central role in maintaining systemic energy homeostasis by produc ing glucose and ketones in processes fueled by oxidation of fatty acids liberated from adipose tissue
The fed and fasted expression of monoacylglycerol acyltransferase 1 (Mogat1) was markedly diminished in whole-body PPAR -null mice compared with wildtype controls, whereas Mogat2 expression tended to be increased in whole-body PPAR -null mice in both fed and fasted conditions (Fig. 1D)
These data demonstrate that Mogat1, but not Mogat2, is induced in liver by fasting and that its expression is highly dependent on PPAR

Summary

Introduction

The liver plays a central role in maintaining systemic energy homeostasis by produc ing glucose and ketones in processes fueled by oxidation of fatty acids liberated from adipose tissue. In mice, this is ac companied by transient hepatic accumulation of glycerolip ids. Suppressing Mogat expression in liver and adipose tissue with antisense oligonucleotides (ASOs) reduced hepatic MGAT activity and triglyceride content com pared with fasted controls. The liver must convert these substrates into glucose and ketones for energy use in extrahepatic tissues, most notably the brain, via processes that are fueled by high level fatty acid oxidation. MGAT activity increases in liver during times of high fat oxidation in multiple animal models and has been suggested to retain essential fatty acids by preventing their

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