HBV-Induced Pyruvate Increases Lactylation of Pyruvate Kinase M2 (PKM2) at K206 to Promote Liver Fibrosis.

Abstract

We previously demonstrated that HBV promotes liver fibrosis through the enhanced production of pyruvate. Pyruvate kinase M2 (PKM2), a key enzyme in pyruvate metabolism, plays an important role in liver fibrogenesis. Recently, lactylation of PKM2 has been identified, which contributes to stabilize its catalytically active tetrameric conformation. Therefore, we hypothesize that PKM2 lactylation is involved in the regulation of HBV-induced liver fibrosis. In this study, we found that sera lactate levels were increased in CHB patients and HBV-Tg mice. Moreover, the lysine lactylation levels of proteins in liver tissues were significantly increased in the HBV-Tg mice. In LX2 cells, we found that pyruvate treatment significantly increased the profibrotic gene expression and lactylation level of PKM2, which promoted its tetramer-to-dimer transition, inhibited its pyruvate kinase activity, and facilitated its nuclear distribution. Through immunoprecipitation, we identified that pyruvate induced PKM2 lactylation at the K206 site. PKM2 knockdown or K206 mutation reduced PKM2 lactylation and abrogated the induction of profibrotic gene expression by pyruvate. Collectively, our findings indicate that HBV infection stimulated pyruvate production, which increased PKM2 lactylation at K206 to promote the expression of profibrogenic genes in HSCs, leading to liver fibrogenesis.