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HBV-Induced Pyruvate Increases Lactylation of Pyruvate Kinase M2 (PKM2) at K206 to Promote Liver Fibrosis
Wenxian Wen1,2, Qin Du1,2, Shuhan Li2
1Department of Clinical Medicine, North Sichuan Medical College, Nanchong 637000, China.
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.
Insights
Hepatitis B virus (HBV) infection boosts pyruvate production, leading to increased PKM2 lactylation. This process promotes liver fibrosis by enhancing profibrogenic gene expression in hepatic stellate cells.
Area of Science:
- Biochemistry
- Hepatology
- Molecular Biology
Background:
- Hepatitis B virus (HBV) infection is a major cause of liver fibrosis.
- Pyruvate metabolism, particularly the role of pyruvate kinase M2 (PKM2), is implicated in liver fibrogenesis.
- PKM2 lactylation stabilizes its active tetrameric form and is a recent discovery.
Purpose of the Study:
- To investigate the role of PKM2 lactylation in HBV-induced liver fibrosis.
- To determine if PKM2 lactylation is a regulatory mechanism in the progression of liver fibrosis.
Main Methods:
- Measurement of lactate levels in sera from CHB patients and HBV-transgenic (HBV-Tg) mice.
- Assessment of protein lysine lactylation in liver tissues of HBV-Tg mice.
- In vitro studies using LX2 cells treated with pyruvate to analyze PKM2 expression, lactylation, activity, and cellular localization.
- Immunoprecipitation to identify the specific site of PKM2 lactylation.
- PKM2 knockdown and site-directed mutagenesis (K206) experiments.
Main Results:
- Elevated serum lactate levels were observed in CHB patients and HBV-Tg mice.
- Increased global protein lysine lactylation in the liver tissues of HBV-Tg mice.
- Pyruvate treatment in LX2 cells enhanced profibrotic gene expression and PKM2 lactylation.
- Pyruvate-induced PKM2 lactylation promoted its tetramer-to-dimer transition, inhibited its enzymatic activity, and facilitated nuclear translocation.
- Pyruvate was identified to induce PKM2 lactylation specifically at the K206 site.
- PKM2 knockdown or K206 mutation attenuated pyruvate-induced PKM2 lactylation and profibrotic gene expression.
Conclusions:
- HBV infection stimulates pyruvate production, which in turn enhances PKM2 lactylation at K206.
- PKM2 lactylation promotes the expression of profibrogenic genes in hepatic stellate cells (HSCs).
- This mechanism contributes significantly to the development of liver fibrogenesis in the context of HBV infection.
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