Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance.

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Lactate has been recently reported to accumulate in the liver with the progression of hepatosteatosis to non-alcoholic steatohepatitis (NASH). However, the underlying mechanism(s) for lactate accumulation and the role of lactate in the NAFLD progression is essentially unknown.Acetylome of normal, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH) samples of human livers were compared to determine the potential acetylated target of lactate metabolism. The interaction of acetylated target and acetyltransferase was measured in multiple cell lines. Inhibitor of the acetyltransferase were injected to high-fat diet (HFD) fed mouse to determine the function of lactate on NAFLD progression in vivo.Hyperacetylation of lactate dehydrogenase B (LDHB) was found to be associated with lactate accumulation in NAFL and NASH livers in human and mouse. P300/CBP-associated factor (PCAF)-mediated acetylation of LDHB K82 was found to significantly decreased LDHB activity and impaired hepatic lactate clearance, resulting in lactate accumulation in NAFLD progression. Acetylated LDHB-induced lactate accumulation exacerbated lipid deposition and inflammatory responses via activating histone hyperacetylation in HFD-induced NASH. The administration of embelin, the inhibitor of the PCAF and the generation of an acetylation-deficient mutant of LDHB ameliorated NASH.PCAF-dependent LDHB acetylation plays a key role in the development of hepatic lipid accumulation and inflammatory responses by imparing lactate clearance; and might be a potential therapeutic target for treatment of NASH.


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