Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA; Research and Development Section, Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
Cell Metab. 2023 Aug 8;35(8):1406-1423.e8. doi: 10.1016/j.cmet.2023.06.013. Epub 2023 Jul 17.
Lactate was implicated in the activation of hepatic stellate cells (HSCs). However, the mechanism by which lactate exerts its effect remains elusive. Using RNA-seq and CUT&Tag chromatin profiling, we found that induction of hexokinase 2 (HK2) expression in activated HSCs is required for induced gene expression by histone lactylation but not histone acetylation. Inhibiting histone lactylation by Hk2 deletion or pharmacological inhibition of lactate production diminishes HSC activation, whereas exogenous lactate but not acetate supplementation rescues the activation phenotype. Thus, lactate produced by activated HSCs determines the HSC fate via histone lactylation. We found that histone acetylation competes with histone lactylation, which could explain why class I HDAC (histone deacetylase) inhibitors impede HSC activation. Finally, HSC-specific or systemic deletion of HK2 inhibits HSC activation and liver fibrosis in vivo. Therefore, we provide evidence that HK2 may be an effective therapeutic target for liver fibrosis.
乳酸被认为与肝星状细胞（HSCs）的激活有关。然而，乳酸发挥作用的机制仍不清楚。使用 RNA-seq 和 CUT&Tag 染色质谱分析，我们发现激活的 HSCs 中己糖激酶 2（HK2）表达的诱导对于组蛋白乳酰化而非组蛋白乙酰化诱导的基因表达是必需的。通过 Hk2 缺失或抑制乳酸产生的药理学抑制来抑制组蛋白乳酰化，可减弱 HSC 的激活，而外源性乳酸而非醋酸盐的补充可挽救激活表型。因此，激活的 HSCs 产生的乳酸通过组蛋白乳酰化决定 HSC 的命运。我们发现组蛋白乙酰化与组蛋白乳酰化竞争，这可以解释为什么 I 类组蛋白去乙酰化酶（HDAC）抑制剂会阻碍 HSC 的激活。最后，HSC 特异性或系统性敲除 HK2 可抑制体内 HSC 的激活和肝纤维化。因此，我们提供的证据表明，HK2 可能是肝纤维化的有效治疗靶点。
