Pyruvate Kinase M2 Tetramerization Protects against Hepatic Stellate Cell Activation and Liver Fibrosis.
Acetylation
Animals
Cyclin D1
/ metabolism
Female
Hepatic Stellate Cells
/ enzymology
Histones
/ metabolism
Humans
Liver Cirrhosis
/ enzymology
Male
Mice
Organic Chemicals
/ pharmacology
Protein Multimerization
Proto-Oncogene Proteins c-myc
/ metabolism
Pyridazines
Pyrroles
Pyruvate Kinase
/ metabolism
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
26
01
2020
revised:
04
08
2020
accepted:
06
08
2020
pubmed:
18
8
2020
medline:
2
12
2020
entrez:
18
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32805235
pii: S0002-9440(20)30372-2
doi: 10.1016/j.ajpath.2020.08.002
pmc: PMC7786052
pii:
doi:
Substances chimiques
CCND1 protein, human
0
Ccnd1 protein, mouse
0
Histones
0
ML-265
0
MYC protein, human
0
Myc protein, mouse
0
Organic Chemicals
0
Proto-Oncogene Proteins c-myc
0
Pyridazines
0
Pyrroles
0
Cyclin D1
136601-57-5
Pyruvate Kinase
EC 2.7.1.40
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2267-2281Subventions
Organisme : NIAID NIH HHS
ID : R01 AI155140
Pays : United States
Informations de copyright
Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Références
Lancet. 2008 Mar 8;371(9615):838-51
pubmed: 18328931
Cell. 2012 Aug 17;150(4):685-96
pubmed: 22901803
FASEB J. 2019 Jul;33(7):8530-8542
pubmed: 30970216
Cell Commun Signal. 2019 Feb 11;17(1):11
pubmed: 30744642
J Pathol. 2003 Jul;200(4):500-3
pubmed: 12845617
Compr Physiol. 2013 Oct;3(4):1473-92
pubmed: 24265236
Cancer Cell. 2018 Mar 12;33(3):368-385.e7
pubmed: 29455928
Sci Rep. 2018 Sep 28;8(1):14517
pubmed: 30266938
Gastroenterology. 2012 Nov;143(5):1319-1329.e11
pubmed: 22885334
Antimicrob Agents Chemother. 2003 Sep;47(9):2810-6
pubmed: 12936978
Biomed Res Int. 2017;2017:2670658
pubmed: 28691020
Circulation. 2017 Dec 19;136(25):2468-2485
pubmed: 28972001
Nat Commun. 2013;4:2823
pubmed: 24264436
Front Cell Dev Biol. 2018 Nov 12;6:150
pubmed: 30483502
Sci Rep. 2017 Mar 06;7:43446
pubmed: 28262670
Hepatology. 2009 Mar;49(3):880-6
pubmed: 19101912
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
FEBS Lett. 2014 Aug 19;588(16):2685-92
pubmed: 24747424
J Hepatol. 2010 Jun;52(6):949-50
pubmed: 20395006
Oncogene. 2011 Oct 20;30(42):4297-306
pubmed: 21516121
Nat Rev Cancer. 2004 Nov;4(11):891-9
pubmed: 15516961
Nature. 2008 Mar 13;452(7184):230-3
pubmed: 18337823
Nature. 2008 Mar 13;452(7184):181-6
pubmed: 18337815
World J Gastroenterol. 2016 Dec 28;22(48):10512-10522
pubmed: 28082803
Nat Chem Biol. 2012 Oct;8(10):839-47
pubmed: 22922757
Biomed Pharmacother. 2016 Dec;84:1858-1864
pubmed: 27894667
Asian Pac J Cancer Prev. 2014;15(5):1961-70
pubmed: 24716919
Nat Commun. 2014 Jul 14;5:4436
pubmed: 25019241
Adv Drug Deliv Rev. 2017 Nov 1;121:3-8
pubmed: 28600202
Nat Commun. 2017 Jan 09;8:14041
pubmed: 28067230
Int J Biochem Cell Biol. 2011 Jul;43(7):969-80
pubmed: 20156581
Diabetes. 2019 Feb;68(2):361-376
pubmed: 30455376
Nat Commun. 2016 Oct 25;7:13280
pubmed: 27779186
Adv Drug Deliv Rev. 2017 Nov 1;121:27-42
pubmed: 28506744
J Clin Invest. 2005 Feb;115(2):209-18
pubmed: 15690074
Cell Metab. 2015 Feb 3;21(2):347
pubmed: 29510100
Clin Cancer Res. 2012 Oct 15;18(20):5554-61
pubmed: 23071357
Kidney Int Suppl. 1996 May;54:S39-45
pubmed: 8731193
Hepatology. 2018 Sep;68(3):1125-1139
pubmed: 29537660
Int J Cell Biol. 2013;2013:242513
pubmed: 23476652
Cell Metab. 2018 May 01;27(5):1156
pubmed: 29719229
Hepatology. 2009 Nov;50(5):1512-23
pubmed: 19790269
Am J Transl Res. 2016 Jun 15;8(6):2820-5
pubmed: 27398165
Genomics. 2004 Dec;84(6):1014-20
pubmed: 15533718
Ernst Schering Found Symp Proc. 2007;(4):99-124
pubmed: 18811055
J Biol Chem. 1986 Oct 15;261(29):13807-12
pubmed: 3020052
Cancer Res. 2010 Nov 15;70(22):8977-80
pubmed: 20978194
Hepatology. 2006 May;43(5):1109-17
pubmed: 16628633
Nat Protoc. 2015 Feb;10(2):305-15
pubmed: 25612230
N Engl J Med. 2011 Sep 22;365(12):1118-27
pubmed: 21992124
J Gastroenterol Hepatol. 2014 Mar;29(3):623-32
pubmed: 24303948