AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice

Lionel Carneiro (1) , Mohamed Asrih (2) , Cendrine Repond (3) , Christine Sempoux (4) , Jean-Christophe Stehle , Corinne Leloup (1) , François R. Jornayvaz (2) , Luc Pellerin (5)

1 CSGA - Centre des Sciences du Goût et de l'Alimentation [Dijon]
2 Service d'Endocrinologie, Diabétologie et Métabolisme
3 Department of Physiology
4 UCL - Université Catholique de Louvain = Catholic University of Louvain
5 Département de Physiologie

Objective: Hepatic steatosis is the first step leading to non-alcoholic fatty liver disease, which represents a major complication of obesity. Here, we show that MCT1 haploinsufficient mice resist to hepatic steatosis development when fed a high fat diet. They exhibit a reduced hepatic capacity to metabolize monocarboxylates such as lactate compared to wildtype mice. Methods: To understand how this resistance to steatosis develops, we used HFD fed wildtype mice with hepatic steatosis and MCT1 haploinsufficient mice to study hepatic metabolism. Results: AMPK is constitutively activated in the liver of MCT1 haploinsufficient mice, leading to an inactivation of SREBP1. Therefore, expression of key transcription factors for lipid metabolism, such as PPARα and γ, CHREB, or SREBP1 itself, as well as several enzymes including FAS and CPT1, was not upregulated in these mice when fed a high fat diet. It is proposed that reduced hepatic lactate metabolism is responsible for the protection against hepatic steatosis in MCT1 haploinsufficient mice via a constitutive activation of AMPK and repression of several major elements involved in hepatic lipid metabolism. Conclusion: Our results support a role of increased lactate uptake in hepatocytes during HFD that, in turn, induce a metabolic shift stimulating SREBP1 activity and lipid accumulation. AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice (PDF Download Available). Available from: https://www.researchgate.net/publication/320544573_AMPK_activation_caused_by_reduced_liver_lactate_metabolism_protects_against_hepatic_steatosis_in_MCT1_haploinsufficient_mice [accessed Jan 16 2018].

Mots clés: AMPK; Hepatic steatosis

Domaines: Médecine humaine et pathologie

Lionel Carneiro, Mohamed Asrih, Cendrine Repond, Christine Sempoux, Jean-Christophe Stehle, et al.. AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice. Molecular metabolism, 2017, 6 (12), pp.1625 - 1633. ⟨10.1016/j.molmet.2017.10.005⟩. ⟨hal-01685459⟩