Methyl-CpG-binding protein 2 facilitates progression of metabolic dysfunction-associated fatty liver disease via lactylation.

BACKGROUND: The incidence and mortality rates of metabolic dysfunction-associated fatty liver disease (MAFLD) have been steadily increasing. Lactylation, a post-translational modification, has been implicated in lipid metabolism disorders. This study aimed to investigate the role of lactylation in the development of MAFLD and to elucidate the underlying mechanisms. METHODS: The relationship between lactate, lactylation, and MAFLD was explored using clinical MAFLD samples from First People's Hospital of Kunming City between March 2021 and September 2024. Proteomic sequencing of these samples was performed, and key proteins were identified by intersecting differentially expressed proteins in MAFLD with differentially modified lactylation sites. Subsequently, an in vitro cellular model of MAFLD was established. The involvement of the key gene methyl-CpG-binding protein 2 (MeCP2) in the MAFLD-lactylation mechanism was assessed using various techniques, including the CCK-8 assay, Oil Red O staining, Bodipy 493/503 fluorescence staining, Western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and co-immunoprecipitation (CO-IP). RESULTS: The key gene MeCP2 was identified by intersecting differentially expressed proteins in MAFLD with lactylation-modified proteins. In MAFLD liver tissue, we observed lactate accumulation, increased lactylation, and elevated MeCP2 expression. In the in vitro MAFLD cell model, lactate was found to promote lactylation, increase MeCP2 expression, and facilitate progression in a dose-dependent manner. Interference with MeCP2 expression inhibited acetyl-CoA carboxylase/fatty acid synthase (ACC/FAS)-mediated lipogenesis while enhancing peroxisome proliferator-activated receptor-α (PPARα)-mediated lipid oxidation. Furthermore, MeCP2 was found to interact with the lactylation-associated protein pan-Kla. Inhibition of MeCP2 suppressed lipid formation by reducing lactylation, thus ameliorating the progression of MAFLD. CONCLUSIONS: Targeting MeCP2 expression improves the pathophysiology of MAFLD by downregulating lactylation, inhibiting ACC/FAS-mediated lipid synthesis, and promoting PPARα-mediated lipid oxidation.