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Cited by 241Liver physiology and pathologyLiver Disease Diagnosis and TreatmentCardiac Fibrosis and Remodeling

FSTL1 promotes liver fibrosis by reprogramming macrophage function through modulating the intracellular function of PKM2

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Rao, Jianhua, Wang, Hao, Ni, Ming, Wang, Zeng, Wang, Ziyi, Wei, Song, Liu, Mu, Wang, Peng +7 more·2022·Gut
DOI 10.1136/gutjnl-2021-325150PMC PMC9664121
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Abstract

Objective: Follistatin-like protein 1 (FSTL1) is widely recognised as a secreted glycoprotein, but its role in modulating macrophage-related inflammation during liver fibrosis has not been documented. Herein, we aimed to characterise the roles of macrophage FSTL1 in the development of liver fibrosis. Design: Expression analysis was conducted with human liver samples obtained from 33 patients with liver fibrosis and 18 individuals without fibrosis serving as controls. Myeloid-specific FSTL1-knockout (FSTL1 M-KO ) mice were constructed to explore the function and mechanism of macrophage FSTL1 in 3 murine models of liver fibrosis induced by carbon tetrachloride injection, bile duct ligation or a methionine-deficient and choline-deficient diet. Results: FSTL1 expression was significantly elevated in macrophages from fibrotic livers of both humans and mice. Myeloid-specific FSTL1 deficiency effectively attenuated the progression of liver fibrosis. In FSTL1 M-KO mice, the microenvironment that developed during liver fibrosis showed relatively less inflammation, as demonstrated by attenuated infiltration of monocytes/macrophages and neutrophils and decreased expression of proinflammatory factors. FSTL1 M-KO macrophages exhibited suppressed proinflammatory M1 polarisation and nuclear factor kappa B pathway activation in vivo and in vitro. Furthermore, this study showed that, through its FK domain, FSTL1 bound directly to the pyruvate kinase M2 (PKM2). Interestingly, FSTL1 promoted PKM2 phosphorylation and nuclear translocation, reduced PKM2 ubiquitination to enhance PKM2-dependent glycolysis and increased M1 polarisation. Pharmacological activation of PKM2 (DASA-58) partially countered FSTL1-mediated glycolysis and inflammation. Conclusion: Macrophage FSTL1 promotes the progression of liver fibrosis by inducing M1 polarisation and inflammation based on the intracellular PKM2 reprogramming function of macrophages.

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  • PKM2 activation and decreased ubiquitination enhance glycolysis flux and promote pro-fibrotic polarization.

    “Its deacetylation reduces lactate production and attenuates liver fibrosis (24), whereas PKM2 activation and decreased ubiquitination enhance glycolysis flux and promote pro-fibrotic polarization (25).”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [25]

    The Discussion reports that FSTL1 inhibits PKM2 ubiquitin-mediated degradation and promotes PKM2 phosphorylation, nuclear translocation, glycolysis, and M1 macrophage polarisation during liver fibrosis. But the Results section headed “PKM2 activator inhibits FSTL1-mediated M1 polarisation and glycolysis in macrophages” reports that the PKM2 activator DASA-58 reverses the increases in glycolysis and M1 polarisation. The claim therefore conflates PKM2 phosphorylation and stabilisation with pharmacological PKM2 activation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Macrophages are critical effector cells involved in both the progression and resolution of fibrosis.

    “Macrophages are critical effector cells involved in both the progression and resolution of fibrosis (7–9).”

    From Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation (2025) · cites this paper as [8]

    The Introduction and Discussion identify macrophages as key regulators of the progression or resolution of liver fibrosis. The claim omits that liver-specific scope and states the point about fibrosis generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 42

  1. [1]Mokdad AA, Lopez AD, Shahraz S, et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med 2014; 12: 145. 10.1186/s12916-014-0145-y 25242656 PMC4169640 · DOI · Paper page
  2. [2]Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet 2014; 383: 1749– 61. 10.1016/S0140-6736(14)60121-5 24480518 · DOI
  3. [3]Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425– 56. 10.1146/annurev-pathol-011110-130246 21073339 · DOI · Paper page
  4. [4]Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115: 209– 18. 10.1172/JCI24282 15690074 PMC546435 · DOI · Paper page
  5. [5]Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med 2019; 65: 37– 55. 10.1016/j.mam.2018.09.002 30213667 · DOI
  6. [6]Pellicoro A, Ramachandran P, Iredale JP, et al. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 2014; 14: 181– 94. 10.1038/nri3623 24566915 · DOI · Paper page
  7. [8]Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014; 60: 1090– 6. 10.1016/j.jhep.2013.12.025 24412603 · DOI · Paper page
  8. [9]Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14: 397– 411. 10.1038/nrgastro.2017.38 28487545 · DOI · Paper page
  9. [10]Pradere J-P, Kluwe J, De Minicis S, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013; 58: 1461– 73. 10.1002/hep.26429 23553591 PMC3848418 · DOI · Paper page
  10. [11]Hellerbrand C, Stefanovic B, Giordano F, et al. The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo. J Hepatol 1999; 30: 77– 87. 10.1016/s0168-8278(99)80010-5 9927153 · DOI · Paper page
  11. [12]Seki E, De Minicis S, Osterreicher CH, et al. Tlr4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007; 13: 1324– 32. 10.1038/nm1663 17952090 · DOI · Paper page
  12. [13]Miura K, Kodama Y, Inokuchi S, et al. Toll-Like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 2010; 139: 323– 34. 10.1053/j.gastro.2010.03.052 20347818 PMC4631262 · DOI · Paper page
  13. [14]Mattiotti A, Prakash S, Barnett P, et al. Follistatin-Like 1 in development and human diseases. Cell Mol Life Sci 2018; 75: 2339– 54. 10.1007/s00018-018-2805-0 29594389 PMC5986856 · DOI
  14. [15]Geng Y, Dong Y, Yu M, et al. Follistatin-Like 1 (FSTL1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development. Proc Natl Acad Sci U S A 2011; 108: 7058– 63. 10.1073/pnas.1007293108 21482757 PMC3084141 · DOI
  15. [16]Henkel M, Partyka J, Gregory AD, et al. FSTL-1 attenuation causes spontaneous Smoke-Resistant pulmonary emphysema. Am J Respir Crit Care Med 2020; 201: 934– 45. 10.1164/rccm.201905-0973OC 31834999 PMC7159415 · DOI
  16. [17]Peters MMC, Meijs TA, Gathier W, et al. Follistatin-Like 1 in cardiovascular disease and inflammation. Mini Rev Med Chem 2019; 19: 1379– 89. 10.2174/1389557519666190312161551 30864520 · DOI
  17. [18]Chaly Y, Hostager B, Smith S, et al. Follistatin-Like protein 1 and its role in inflammation and inflammatory diseases. Immunol Res 2014; 59: 266– 72. 10.1007/s12026-014-8526-z 24838142 · DOI
  18. [19]Liu Y, Xu J, Liu T, et al. Fstl1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy. BMC Pulm Med 2021; 21: 45. 10.1186/s12890-021-01409-6 33509151 PMC7841997 · DOI
  19. [20]Li G, Ren H, Wu X, et al. Follistatin like protein-1 modulates macrophage polarization and aggravates dextran sodium sulfate-induced colitis. Int Immunopharmacol 2020; 83: 106456. 10.1016/j.intimp.2020.106456 32247265 · DOI
  20. [21]Chaly Y, Fu Y, Marinov A, et al. Follistatin-Like protein 1 enhances NLRP3 inflammasome-mediated IL-1β secretion from monocytes and macrophages. Eur J Immunol 2014; 44: 1467– 79. 10.1002/eji.201344063 24470197 PMC4004659 · DOI
  21. [22]Zheng X, Qi C, Zhang S, et al. TGF-β1 induces Fstl1 via the Smad3-c-Jun pathway in lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2017; 313: L240– 51. 10.1152/ajplung.00523.2016 28495857 · DOI
  22. [23]Dong Y, Geng Y, Li L, et al. Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice. J Exp Med 2015; 212: 235– 52. 10.1084/jem.20121878 25584011 PMC4322044 · DOI
  23. [24]Liu T, Liu Y, Miller M, et al. Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma. Am J Physiol Lung Cell Mol Physiol 2017; 313: L27– 40. 10.1152/ajplung.00510.2016 28473327 · DOI
  24. [25]Zhou X, Xie F, Wang L, et al. The function and clinical application of extracellular vesicles in innate immune regulation. Cell Mol Immunol 2020; 17: 323– 34. 10.1038/s41423-020-0391-1 32203193 PMC7109106 · DOI · Paper page
  25. [26]Yang L, Xie M, Yang M, et al. Pkm2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun 2014; 5: 4436. 10.1038/ncomms5436 25019241 PMC4104986 · DOI
  26. [27]Moylan C, Diehl AM. Expression data for nonalcoholic fatty liver disease patients. gene expression omnibus, 2019. Available: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE49541
  27. [28]Mas VR, Maluf DG, Archer KJ. RMA expression data for liver samples from subjects with HCV, HCV-HCC, or normal liver. gene expression omnibus, 2018. Available: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE14323
  28. [29]Lalloyer F, Bauge E, Pawlak M. Transcriptomic analysis of CLL4-induced liver injury in WT and DpT KO mice. gene expression omnibus, 2019. Available: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE141821
  29. [30]Misu H, Takamura T. Expression data from mouse liver treated with metformin. gene expression omnibus, 2019. Available: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE35961
  30. [31]Gijbels E, Devisscher L, Vinken M. Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. gene expression omnibus, 2020. Available: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15249432 32152650
  31. [32]Li X, Li L, Chang Y, et al. Structural and functional study of FK domain of FSTL1. Protein Sci 2019; 28: 1819– 29. 10.1002/pro.3696 31351024 PMC6739823 · DOI
  32. [33]Wang P, Sun C, Zhu T, et al. Structural insight into mechanisms for dynamic regulation of PKM2. Protein Cell 2015; 6: 275– 87. 10.1007/s13238-015-0132-x 25645022 PMC4383751 · DOI
  33. [34]Dayton TL, Jacks T, Vander Heiden MG. Pkm2, cancer metabolism, and the road ahead. EMBO Rep 2016; 17: 1721– 30. 10.15252/embr.201643300 27856534 PMC5283597 · DOI · Paper page
  34. [35]Luo W, Hu H, Chang R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 2011; 145: 732– 44. 10.1016/j.cell.2011.03.054 21620138 PMC3130564 · DOI · Paper page
  35. [37]Guo J, Ren R, Yao X, et al. Pkm2 suppresses osteogenesis and facilitates adipogenesis by regulating β-catenin signaling and mitochondrial fusion and fission. Aging 2020; 12: 3976– 92. 10.18632/aging.102866 32096765 PMC7066892 · DOI
  36. [39]Xu R, Zhang Z, Wang F-S. Liver fibrosis: mechanisms of immune-mediated liver injury. Cell Mol Immunol 2012; 9: 296– 301. 10.1038/cmi.2011.53 22157623 PMC4132585 · DOI
  37. [40]Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 2014; 59: 2034– 42. 10.1002/hep.26754 24115204 · DOI · Paper page
  38. [41]Ramnath D, Irvine KM, Lukowski SW, et al. Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes. JCI Insight 2018; 3: e120274. 10.1172/jci.insight.120274 PMC6124454 30046009 · DOI
  39. [42]Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 2019; 575):: 512– 8. 10.1038/s41586-019-1631-3 31597160 PMC6876711 · DOI · Paper page
  40. [43]Li D, Wang Y, Xu N, et al. Follistatin-Like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis. Arthritis Res Ther 2011; 13: R17. 10.1186/ar3241 21303509 PMC3241361 · DOI
  41. [44]Fang D, Shi X, Lu T, et al. The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis. Metabolism 2019; 98: 16– 26. 10.1016/j.metabol.2019.05.008 31132382 · DOI
  42. [46]Yang W, Zheng Y, Xia Y, et al. Erk1/2-Dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 2012; 14: 1295– 304. 10.1038/ncb2629 23178880 PMC3511602 · DOI

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Authors
Rao, J., Wang, H., Ni, M., Wang, Z., Wang, Z., Wei, S., Liu, M., Wang, P., Qiu, J., Zhang, L., Wu, C., Shen, H., Wang, X., Cheng, F., & Lu, L.
Affiliations
  • Nanjing Normal University (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • State Key Laboratory of Reproductive Medicine (CN)
  • Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China
ORCID
Venue
Gut
Publisher
BMJ
Published
2022-02-09
Volume
71
Issue
12
Pages
2539-2550
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
DOI
10.1136/gutjnl-2021-325150
PMC
PMC9664121
OpenAlex
W4210895382
Cited by
241
References
6
Citations by year
2026: 42 · 2025: 72 · 2024: 85 · 2023: 31 · 2022: 11
FWCI
29.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Gut (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • The Six talent peaks project in Jiangsu Province (2017-WSW-019)
  • the CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-035)
  • National Natural Science Foundation of China (81871259, 81971495, 82070675)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
FSTL1, liver fibrosis, macrophages, PKM2, M1 macrophage polarization, inflammation, glycolysis, NF-κB signaling, myeloid-specific knockout, carbon tetrachloride, bile duct ligation, ubiquitination, nuclear translocation
MeSH terms
Animals, Humans, Inflammation, Liver, Liver Cirrhosis, Macrophages, Mice, Inbred C57BL, Pyruvate Kinase, Follistatin-Related Proteins, Mice

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