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.