Pyruvate kinase M2 tetramerization protects against hepatic stellate cell activation and liver fibrosis
Pyruvate kinase M2 tetramerization protects against hepatic stellate cell activation and liver fibrosis
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丙酮酸激酶 M2 四聚化可防止肝星状细胞活化和肝纤维化
DOI：
10.1016/j.ajpath.2020.08.002
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hong Jian
中科院分区：
文献类型：
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作者：
Zheng D;an;Jiang Yuchuan;Qu Chen;Yuan Hui;Hu Kaishun;He Lu;Chen Peng;Li Jinying;Tu Mengxian;Lin Lehang;Chen Hengxing;Lin Zelong;Lin Wenyu;Fan Jun;Cheng Guohua;Hong Jian
肝纤维化是全球范围内日益严重的健康问题，目前尚无有效的抗纤维化药物。虽然有氧糖酵解参与了肝星状细胞（HSC）的活化，但丙酮酸激酶M2（PKM 2）在肝纤维化中的作用仍不清楚。我们检测了PKM 2在肝组织和原代肝细胞中的表达和定位。采用肝星状细胞和肝纤维化小鼠模型，研究PKM 2拮抗剂紫草素及其变构剂TEPP-46的体内外抗肝纤维化作用。染色质免疫沉淀测序和免疫沉淀进行，以确定相关的分子机制。与正常肝脏相比，PKM 2表达在小鼠和人类纤维化肝脏中均显著上调，并且主要在活化的而不是静止的HSC中检测到。PKM 2基因敲低可明显抑制HSC的活化和增殖。有趣的是，PKM 2二聚体，而不是四聚体，诱导HSC活化。TEPP-46诱导的PKM 2四聚化通过调节组蛋白H3 K9乙酰化，有效抑制HSC活化，减少有氧糖酵解，降低MYCandCCND 1表达。TEPP-46和紫草素在体内显著减轻肝纤维化。我们的研究结果表明PKM 2在肝纤维化中的非代谢作用。PKM 2四聚化或抑制可防止HSC活化并防止肝纤维化。
Liver fibrosis is an increasing health problem worldwide, for which no effective antifibrosis drugs are available. Although the involvement of aerobic glycolysis in hepatic stellate cell (HSC) activation has been reported, the role of pyruvate kinase M2 (PKM2) in liver fibrogenesis still remains unknown. We examined PKM2 expression and location in liver tissues and primary hepatic cells. Thein vitroandin vivoeffects of a PKM2 antagonist (shikonin) and its allosteric agent (TEPP-46) on liver fibrosis were investigated in HSCs and liver fibrosis mouse model. Chromatin immunoprecipitation sequencing and immunoprecipitation were performed to identify the relevant molecular mechanisms. PKM2 expression was significantly up-regulated in both mouse and human fibrotic livers compared with normal livers, and mainly detected in activated, rather than quiescent, HSCs. PKM2 knockdown markedly inhibited the activation and proliferation of HSCsin vitro. Interestingly, the PKM2 dimer, rather than the tetramer, induced HSC activation. PKM2 tetramerization induced by TEPP-46 effectively inhibited HSC activation, reduced aerobic glycolysis, and decreasedMYCandCCND1expression via regulating histone H3K9 acetylation in activated HSCs. TEPP-46 and shikonin dramatically attenuated liver fibrosisin vivo. Our findings demonstrate a nonmetabolic role of PKM2 in liver fibrosis. PKM2 tetramerization or suppression could prevent HSC activation and protects against liver fibrosis.