AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo.

Marc Foretz,Benoit Viollet,Patrick Even

doi:10.3390/ijms19092826

Abstract

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver, achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

Highlights

AMP-activated protein kinase (AMPK) is a phylogenetically conserved serine/threonine protein kinase viewed as a fuel gauge monitoring systemic and cellular energy status which plays a crucial role in protecting cellular function under energy-restricted conditions [1]
By using a genetic mouse model expressing in the liver a gain-of-function AMPKγ1 mutant, Woods et al demonstrated that the effect of hepatic AMPK activation in the protection against hepatic steatosis is largely dependent on the suppression of de novo lipogenesis, but not on the stimulation of hepatic fatty acid oxidation [10]
Further support for a significant role of lipid oxidation following hepatic AMPK activation recently came from a study investigating the therapeutic beneficial of the β1-biased activator PF-06409577 in a high-fat-fed mouse model, where the contribution of de novo lipogenesis is essentially negligible for hepatic TG accumulation [7]

Summary

Introduction

AMP-activated protein kinase (AMPK) is a phylogenetically conserved serine/threonine protein kinase viewed as a fuel gauge monitoring systemic and cellular energy status which plays a crucial role in protecting cellular function under energy-restricted conditions [1]. By inhibiting ACC and lowering the concentration of its reaction product malonyl-CoA, AMPK activation is expected to coordinate the partitioning of fatty acids between oxidative and biosynthetic pathways by increasing fatty acid oxidation (FAO) capacity and inhibiting de novo lipogenesis (DNL), respectively. For these reasons, AMPK has emerged as a promising therapeutic target to treat metabolic disorders that occur in conditions such as nonalcoholic fatty liver disease (NAFLD). In the present study, we examined the impact of AMPK activation in the liver on hepatic lipid metabolism and determined its effect on FAO rates in vivo, measured by indirect calorimetry

Methods

Results

Conclusion