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

Lionel Carneiro, Mohamed Asrih, Cendrine Repond, Christine Sempoux, Jean-Christophe Stehle, Corinne Leloup, François R. Jornayvaz, Luc Pellerin


Hepatic steatosis can evolve into non-alcoholic fatty liver disease (NAFLD). Monocarboxylate transporter isoform 1 (MCT1) haploinsufficient mice (MCT1+/-) exhibit resistance to high-fat diet-induced obesity and associated NAFLD. Carneiro et al. reinforce the concept that AMP-activated protein kinase (AMPK) activation mediates this effect and promotes a protection against hepatic steatosis by inhibiting Sterol Regulatory Element Binding Protein 1 (SREBP1). They also reveal an unexpected regulatory role of circulating lactate in the regulation of hepatic lipid metabolism.

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.

Conclusions: 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.