High-intensity interval training induces lactate dehydrogenase B lactylation to inhibit hepatic lipogenesis to alleviate metabolic dysfunction-associated fatty liver disease.

BACKGROUND

De novo lipogenesis (DNL) is an important cause of lipid deposition in metabolic dysfunction-associated fatty liver disease (MAFLD), and recent studies report that lactate is a major substrate for DNL in MAFLD. High-intensity interval training (HIIT) has a powerful regulatory effect on lactate metabolism, but whether it can alleviate MAFLD by regulating lactate metabolism has not been reported.

METHODS

High-fat diet (HFD)-induced MAFLD mice were used as a model and underwent performed 8 weeks of HIIT. Serum and liver tissues were collected and analysed by biochemical assay, histology, quantitative real-time polymerase chain reaction, western blot, coimmunoprecipitation, isotope tracing and ultra-performance liquid chromatography-tandem mass spectrometry analysis. HepG2 cells were treated in vitro with oleic acid/palmitic acid (OA/PA) to mimic/inhibit lactate dehydrogenase B (LDHB) lactylation (Kla) by mutations and to observe changes in lipid deposition.

RESULTS

Here, hepatic lactate metabolism in MAFLD mice is characterised by increased endogenous lactate and involvement in DNL. In contrast, decreased hepatic lipid deposition in MAFLD mice after HIIT inhibits lactate-involved DNL, and lactate enters the tricarboxylic acid cycle with increased oxidative catabolism. MAFLD model mice have decreased LDHB Kla and increased LDHB activity in liver and OA/PA-induced hepatocytes. LDHB lactylation increases and LDHB activity decreases after HIIT. LDHB K82 is a lactylation site that affects LDHB activity, and in vitro LDHB K82 lactylation inhibition increases LDHB activity, leading to OA/PA-induced lipid deposition in HepG2 cells, whereas LDHB K82La enhancement decreases lipid deposition.

CONCLUSIONS

HIIT effectively alleviates HFD-induced MAFLD in mice by regulating hepatic lactate metabolism to inhibit lactate-substrate DNL, and the ability of LDHB K82La to regulate LDHB activity may be one of the mechanisms by which HIIT exerts the above effects.