2. Academic Validation
  3. 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

  • Am J Pathol. 2020 Nov;190(11):2267-2281. doi: 10.1016/j.ajpath.2020.08.002.
Dandan Zheng 1,  Yuchuan Jiang 1,  Chen Qu 1,  Hui Yuan 1,  Kaishun Hu 2,  Lu He 1,  Peng Chen 1,  Jinying Li 3,  Mengxian Tu 1,  Lehang Lin 2,  Hengxing Chen 2,  Zelong Lin 1,  Wenyu Lin 4,  Jun Fan 5,  Guohua Cheng 6,  Jian Hong 7
Affiliations

Affiliations

  • 1 Department of Abdominal Surgery, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Gastroenterology, the First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 4 Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 5 Departments of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, China.
  • 6 Department of Pharmacy, College of Pharmacy, Jinan University, Guangzhou, China.
  • 7 Department of Abdominal Surgery, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China; Pathophysiology, School of Medicine, Jinan University, Guangzhou, China. Electronic address: jhong7@smu.edu.cn.
PMID: 32805235 DOI: 10.1016/j.ajpath.2020.08.002
Abstract

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. The in vitro and in vivo effects 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 HSCs in 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 decreased MYC and CCND1 expression via regulating histone H3K9 acetylation in activated HSCs. TEPP-46 and shikonin dramatically attenuated liver fibrosis in 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.

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