Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways

Acta Pharmacologica Sinica volume 45, pages 988–1001 (2024)Cite this article

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Phosphorylation of FGFR1 is increased in macrophages in the liver of HFD-fed mice.
Fig. 2: Macrophage-specific FGFR1 knockout protects against HFD-induced fibrosis and lipid accumulation in liver.
Fig. 3: Macrophage-specific FGFR1 knockout prevents HFD-induced liver inflammation by suppressing MAPK and TNF signaling pathways.
Fig. 4: FGFR1 deficiency suppresses PA-induced inflammatory responses in macrophages.
Fig. 5: Factors released from PA-stimulated macrophages cause lipid accumulation and inflammatory responses in hepatocytes via an FGFR1-dependent manner.
Fig. 6: FGFR1 is required for macrophages to activate hepatic stellate cells.
Fig. 7: FGFR1 inhibitor alleviates HFD-induced liver injury.
Fig. 8: FGFR1 inhibitor prevents HFD-induced liver inflammation through inhibiting the activation of MAPK and TNF pathways.

Similar content being viewed by others

References

  1. Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27:R1147–R51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pineiro-Carrero VM, Pineiro EO. Liver. Pediatrics. 2004;113:1097–106.

    Article  PubMed  Google Scholar 

  3. Younossi ZM. Non-alcoholic fatty liver disease—a global public health perspective. J Hepatol. 2019;70:531–44.

    Article  PubMed  Google Scholar 

  4. Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet. 2021;397:2212–24.

    Article  CAS  PubMed  Google Scholar 

  5. Barreby E, Chen P, Aouadi M. Macrophage functional diversity in NAFLD—more than inflammation. Nat Rev Endocrinol. 2022;18:461–72.

    Article  CAS  PubMed  Google Scholar 

  6. Gordon S. The macrophage. Bioessays. 1995;17:977–86.

    Article  CAS  PubMed  Google Scholar 

  7. Alisi A, Carpino G, Oliveira FL, Panera N, Nobili V, Gaudio E. The role of tissue macrophage-mediated inflammation on NAFLD pathogenesis and its clinical implications. Mediators Inflamm. 2017;2017:8162421.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29.

    Article  CAS  PubMed  Google Scholar 

  9. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16:139–49.

    Article  CAS  PubMed  Google Scholar 

  10. Wang S, Cao S, Arhatte M, Li D, Shi Y, Kurz S, et al. Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice. Nat Commun. 2020;11:2303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Choi Y, Jang S, Choi MS, Ryoo ZY, Park T. Increased expression of FGF1-mediated signaling molecules in adipose tissue of obese mice. J Physiol Biochem. 2016;72:157–67.

    Article  CAS  PubMed  Google Scholar 

  12. Wang C, Li Y, Li H, Zhang Y, Ying Z, Wang X, et al. Disruption of FGF signaling ameliorates inflammatory response in hepatic stellate cells. Front Cell Dev Biol. 2020;8:601.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Arangalage D, Degrauwe N, Michielin O, Monney P, Ozdemir BC. Pathophysiology, diagnosis and management of cardiac toxicity induced by immune checkpoint inhibitors and BRAF and MEK inhibitors. Cancer Treat Rev. 2021;100:102282.

    Article  CAS  PubMed  Google Scholar 

  14. Diecke S, Quiroga-Negreira A, Redmer T, Besser D. FGF2 signaling in mouse embryonic fibroblasts is crucial for self-renewal of embryonic stem cells. Cells Tissues Organs. 2008;188:52–61.

    Article  CAS  PubMed  Google Scholar 

  15. Li D, Xia L, Huang P, Wang Z, Guo Q, Huang C, et al. Cancer-associated fibroblast-secreted IGFBP7 promotes gastric cancer by enhancing tumor associated macrophage infiltration via FGF2/FGFR1/PI3K/AKT axis. Cell Death Discov. 2023;9:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72:2045–56.

    Article  CAS  PubMed  Google Scholar 

  17. Pan Y, Wang Y, Cai L, Cai Y, Hu J, Yu C, et al. Inhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats. Br J Pharmacol. 2012;166:1169–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Charni-Natan M, Goldstein I. Protocol for primary mouse hepatocyte isolation. STAR Protoc. 2020;1:100086.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Raj T, Kanellakis P, Pomilio G, Jennings G, Bobik A, Agrotis A. Inhibition of fibroblast growth factor receptor signaling attenuates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2006;26:1845–51.

    Article  CAS  PubMed  Google Scholar 

  20. Liu X, Mashour GA, Webster HF, Kurtz A. Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin. Glia. 1998;24:390–7.

    Article  CAS  PubMed  Google Scholar 

  21. Pinto AR, Godwin JW, Chandran A, Hersey L, Ilinykh A, Debuque R, et al. Age-related changes in tissue macrophages precede cardiac functional impairment. Aging (Albany NY). 2014;6:399–413.

    Article  PubMed  Google Scholar 

  22. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145–59.

    Article  CAS  PubMed  Google Scholar 

  24. Xu L, Liu W, Bai F, Xu Y, Liang X, Ma C, et al. Hepatic macrophage as a key player in fatty liver disease. Front Immunol. 2021;12:708978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature. 2014;505:97–102.

    Article  PubMed  Google Scholar 

  26. Webster JD, Vucic D. The balance of TNF mediated pathways regulates inflammatory cell death signaling in healthy and diseased tissues. Front Cell Dev Biol. 2020;8:365.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang Y, Wu B, Zhang H, Ge X, Ying S, Hu M, et al. Inhibition of MD2-dependent inflammation attenuates the progression of non-alcoholic fatty liver disease. J Cell Mol Med. 2018;22:936–47.

    Article  CAS  PubMed  Google Scholar 

  28. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate immunity and inflammation in NAFLD/NASH. Dig Dis Sci. 2016;61:1294–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Smith BK, Marcinko K, Desjardins EM, Lally JS, Ford RJ, Steinberg GR. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am J Physiol Endocrinol Metab. 2016;311:E730–E40.

    Article  PubMed  Google Scholar 

  30. Gao J, Wei B, de Assuncao TM, Liu Z, Hu X, Ibrahim S, et al. Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis. J Hepatol. 2020;73:1144–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021;18:151–66.

    Article  PubMed  Google Scholar 

  32. Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-beta in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells. 2019;8:1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cheng Q, Li C, Yang CF, Zhong YJ, Wu D, Shi L, et al. Methyl ferulic acid attenuates liver fibrosis and hepatic stellate cell activation through the TGF-beta1/Smad and NOX4/ROS pathways. Chem Biol Interact. 2019;299:131–9.

    Article  CAS  PubMed  Google Scholar 

  34. Lee YS, Wollam J, Olefsky JM. An integrated view of immunometabolism. Cell. 2018;172:22–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ying W, Fu W, Lee YS, Olefsky JM. The role of macrophages in obesity-associated islet inflammation and beta-cell abnormalities. Nat Rev Endocrinol. 2020;16:81–90.

    Article  PubMed  Google Scholar 

  36. Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology. 2014;59:2034–42.

    Article  PubMed  Google Scholar 

  37. Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology. 2009;50:261–74.

    Article  CAS  PubMed  Google Scholar 

  38. Yang B, Luo W, Wang M, Tang Y, Zhu W, Jin L, et al. Macrophage-specific MyD88 deletion and pharmacological inhibition prevents liver damage in non-alcoholic fatty liver disease via reducing inflammatory response. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166480.

    Article  CAS  PubMed  Google Scholar 

  39. Wang Y, Qian Y, Fang Q, Zhong P, Li W, Wang L, et al. Author Correction: Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat Commun. 2018;9:16185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lawan A, Bennett AM. Mitogen-activated protein kinase regulation in hepatic metabolism. Trends Endocrinol Metab. 2017;28:868–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu L, Sun J, Liu L, Du X, Liu Y, Yan X, et al. Anti-toll-like receptor 2 antibody ameliorates hepatic injury, inflammation, fibrosis and steatosis in obesity-related metabolic disorder rats via regulating MAPK and NF-kappaB pathways. Int Immunopharmacol. 2020;82:106368.

    Article  CAS  PubMed  Google Scholar 

  42. Jiang J, Yan L, Shi Z, Wang L, Shan L, Efferth T. Hepatoprotective and anti-inflammatory effects of total flavonoids of Qu Zhi Ke (peel of Citrus Changshan-huyou) on non-alcoholic fatty liver disease in rats via modulation of NF-kappaB and MAPKs. Phytomedicine. 2019;64:153082.

    Article  CAS  PubMed  Google Scholar 

  43. Zhao W, Yan Y, Xiao Z, Wang M, Xu M, Wang Z, et al. Bicyclol ameliorates nonalcoholic fatty liver disease in mice via inhibiting MAPKs and NF-kappaB signaling pathways. Biomed Pharmacother. 2021;141:111874.

    Article  CAS  PubMed  Google Scholar 

  44. Wu L, Wang Y, Chi G, Shen B, Tian Y, Li Z, et al. Morin reduces inflammatory responses and alleviates lipid accumulation in hepatocytes. J Cell Physiol. 2019;234:19785–98.

    Article  CAS  PubMed  Google Scholar 

  45. Huang Y, Wang F, Li H, Xu S, Xu W, Pan X, et al. Inhibition of fibroblast growth factor receptor by AZD4547 protects against inflammation in septic mice. Inflammation. 2019;42:1957–67.

    Article  CAS  PubMed  Google Scholar 

  46. Chen X, Zhang X, Xu J, Zhao Y, Bao J, Zheng Z, et al. AZD4547 attenuates lipopolysaccharide-induced acute kidney injury by inhibiting inflammation: the role of FGFR1 in renal tubular epithelial cells. Drug Des Devel Ther. 2020;14:833–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xu Z, Luo W, Chen L, Zhuang Z, Yang D, Qian J, et al. Ang II (Angiotensin II)-induced FGFR1 (Fibroblast Growth Factor Receptor 1) activation in tubular epithelial cells promotes hypertensive kidney fibrosis and injury. Hypertension. 2022;79:2028–41.

    Article  CAS  PubMed  Google Scholar 

  48. Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015;4:215–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Financial support was provided by the Medical and Health Science Research Project of Zhejiang Province (2023XY164 to LJH, 2022KY348 to WZ), Key Research Project of Wenzhou City (ZY2021021 to YW).

Author information

Authors and Affiliations

  1. Joint Research Center on Medicine, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, 315700, China

    Yan-ni Zhao, Yong-sheng Jiang, Wei Zuo, Li-jiang Huang & Yi Wang

  2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Yan-ni Zhao, Zhou-di Liu, Tao Yan, Ting-xin Xu & Tian-yang Jin

  3. College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, Republic of Korea

    Yan-ni Zhao & Kwang Youl Lee

  4. School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China

    Yi Wang

Authors
  1. Yan-ni Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhou-di Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ting-xin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tian-yang Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong-sheng Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kwang Youl Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Li-jiang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YNZ, ZDL, TY, and YW contributed to the literature search and study design. YNZ, TXX, TYJ, YSJ, WZ, KYL, and YW performed the experiments and analyzed the data. LJH and KYL provided technical help. TXX, TYJ, LJH, and YW participated in the drafting of the article. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

Corresponding authors

Correspondence to Kwang Youl Lee, Li-jiang Huang or Yi Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Yn., Liu, Zd., Yan, T. et al. Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways. Acta Pharmacol Sin 45, 988–1001 (2024). https://doi.org/10.1038/s41401-024-01226-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-024-01226-7

Keywords

Search

Advanced search

Quick links