Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance

TL;DR

This study reveals a new metabolic pathway activated in mice with hereditary fructose intolerance, which could lead to better treatments for the disease.

Contribution

The study identifies AMPD2 activation as a novel metabolic event in hereditary fructose intolerance linked to disease progression.

Findings

AMPD2 activation is a common feature in aldolase B deficient mice exposed to fructose.

Deleting AMPD2 in hepatocytes improves metabolic dysregulation and increases fructose tolerance in mice.

AMPD2 activation is driven by a phosphate trap mechanism in these mice.

Abstract

Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P). No cure exists for HFI and treatment is limited to avoid exposure to fructose and sugar. Using aldolase B deficient mice, here we identify a yet unrecognized metabolic event activated in HFI and associated with the progression of the disease. Besides the accumulation of F1P, here we show that the activation of the purine degradation pathway is a common feature in aldolase B deficient mice exposed to fructose. The purine degradation pathway is a metabolic route initiated by adenosine monophosphate deaminase 2 (AMPD2) that regulates overall energy balance. We demonstrate that very low amounts of fructose are sufficient to activate AMPD2 in these mice via a phosphate trap. While blocking AMPD2 do not impact F1P accumulation and the risk of hypoglycemia, its deletion in hepatocytes markedly improves the metabolic dysregulation induced by fructose and corrects fat and glycogen storage while significantly increasing the voluntary tolerance of these mice to fructose. In summary, we provide evidence for a critical pathway activated in HFI that could be targeted to improve the metabolic consequences associated with fructose consumption.

Differential analysis of the metabolic consequences associated with fructose metabolism in mice with aldolase B deficiency identifies the importance of AMP deamination in a side chain metabolic route driving metabolic dysregulation and inflammation

Figures