Lactate Promotes Liver Regeneration by Increasing Fatty Acid Oxidation Through GCN5-Mediated H3K9 Lactylation.

BACKGROUND & AIMS: Lactylation has been implicated in the repair and regeneration of multiple organs, including the skin and the heart. The liver serves as a vital organ for lactate metabolism, whereas the roles of lactate and lactylation during liver regeneration remain unclear.

METHODS

Mice were subjected to 70% partial hepatectomy, and the liver-to-body weight ratio and proliferative markers were measured. Protein-protein interactions were detected by co-immunoprecipitation. The pivotal site of GCN5 for catalysis was predicted by theoretical modeling. CUT&Tag and bulk RNA sequencing assays were used to identify downstream genes regulated by H3K9 lactylation. Murine hepatocyte organoids and human liver tissues were used to validate the effects of H3K9 lactylation.

RESULTS

Lactate supplementation notably improved the liver-to-body weight ratio and upregulated hepatic levels of Ki-67, proliferating cell nuclear antigen, and 5-ethynyl-2'-deoxyuridine incorporation at 48 hours after partial hepatectomy, whereas hepatocyte-specific Ldha knockout mice showed impaired liver regenerative capacity. In vitro experiments indicated that increased intracellular lactate upregulated H3 lactylation and promoted hepatocyte proliferation. Mechanistically, GCN5, rather than P300 or MOF, was identified as the pivotal enzyme catalyzing H3K9 lactylation. Furthermore, lactate treatment promoted the interaction between GCN5 and H3K9 during liver regeneration. Glu639 was identified as the critical amino acid residue in GCN5 for catalyzing H3K9 lactylation. CUT&Tag and bulk RNA sequencing results further revealed that H3K9 lactylation upregulated the expression of Lipin1 and its mediated transcription of fatty acid oxidation-related genes. The proregenerative effects of lactate and H3K9 lactylation were validated using murine hepatocyte organoids and human liver tissues.

CONCLUSIONS

Lactate facilitates liver regeneration through promoting GCN5-mediated H3K9 lactylation, which upregulates Lipin1 transcription and subsequent Lipin1-mediated fatty acid oxidation in hepatocytes.