美国芝加哥伊利诺伊大学Nissim Hay研究组发现，己糖激酶2 (HK2)通过组蛋白乳酸化介导的基因表达是肝星状细胞(HSC)激活和肝纤维化所必需的。2023年7月17日，国际知名学术期刊《细胞—代谢》发表了这一成果。

通过RNA-seq和CUT&Tag染色质谱分析，他们发现在激活的HSC中诱导HK2表达是通过组蛋白乳酸化而不是组蛋白乙酰化诱导基因表达所必需的。通过Hk2缺失或药物抑制乳酸生成来抑制组蛋白乳酸化会减少HSC的激活，而外源性乳酸而非醋酸盐补充可以恢复激活表型。因此，激活的HSC产生的乳酸通过组蛋白乳酸化决定了HSC的命运。

他们发现组蛋白乙酰化与组蛋白乳酸化相互竞争，这可以解释为什么I类HDAC(组蛋白去乙酰化酶)抑制剂会阻碍HSC的激活。最后，HSC特异性或系统性的HK2缺失在体内抑制HSC激活和肝纤维化。因此，他们提供证据表明HK2可能是肝纤维化的有效治疗靶点。

据悉，乳酸与HSC的激活有关。然而，乳酸发挥其作用的机制尚不清楚。

附：英文原文

Title: Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis

Author: Hyunsoo Rho, Alexander R. Terry, Constantinos Chronis, Nissim Hay

Issue&Volume: 2023-07-17

Abstract: 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 andCUT&Tag chromatin profiling, we found that induction of hexokinase 2 (HK2) expressionin activated HSCs is required for induced gene expression by histone lactylation butnot 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 explainwhy 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.

DOI: 10.1016/j.cmet.2023.06.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00223-1