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Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-β1/Smad signaling pathway

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Abstract

Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (activated HSCs), which produce excessive extracellular matrix. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) exerts protective effects on hepatic inflammation and fibrosis. The current study was to explore the function of PPAR-γ on HSC activation and progression of nonalcoholic steatohepatitis (NASH). Our study found that HSCs were gradually activated during the progression of methionine-choline-deficient (MCD) diet-induced NASH, accompanied by decreased PPAR-γ expression and activated TGF-β1/Smad signaling pathway in the liver. PPAR-γ agonist was found to inhibit primary HSCs and NIH/3T3 fibroblast activation and reverted their phenotypical morphology induced by TGF-β1 in vitro. In addition to this, PPAR-γ agonist decreased expression of TGF-β1 and phosphorylation of Smad2/3 while increased expression of Smad7. In vivo, rosiglitazone, a PPAR-γ agonist, inhibited HSC activation and alleviated liver fibrosis and inflammation similarly via inhibiting the activation of TGF-β1/Smad signaling pathway. In parallel, rosiglitazone alleviated hepatic lipid accumulation and peroxidation, beneficial to reverse of NASH. From these findings, it can be concluded that the gradual activation of HSCs is crucial to the progression of NASH and modulating PPAR-γ expression can affect HSC activation via TGF-β1/Smad signaling pathway and thereby influence hepatic fibrogenesis.

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References

  1. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19:557–566. https://doi.org/10.1038/nm.3159

    Article  CAS  PubMed  Google Scholar 

  2. Arab JP, Cabrera D, Sehrawat TS, Jalan-Sakrikar N, Verma VK, Simonetto D, Cao S, Yaqoob U, Leon J, Freire M, Vargas JI, De Assuncao TM, Kwon JH, Guo Y, Kostallari E, Cai Q, Kisseleva T, Oh Y, Arrese M, Huebert RC, Shah VH (2020) Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12. J Hepatol 73:149–160. https://doi.org/10.1016/j.jhep.2020.02.005

    Article  CAS  PubMed  Google Scholar 

  3. Brandon-Warner E, Benbow JH, Swet JH, Feilen NA, Culberson CR, McKillop IH, deLemos AS, Russo MW, Schrum LW (2018) Adeno-associated virus serotype 2 vector-mediated reintroduction of microRNA-19b attenuates hepatic fibrosis. Hum Gene Ther 29:674–686. https://doi.org/10.1089/hum.2017.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bruschi FV, Claudel T, Tardelli M, Caligiuri A, Stulnig TM, Marra F, Trauner M (2017) The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 65:1875–1890. https://doi.org/10.1002/hep.29041

    Article  CAS  PubMed  Google Scholar 

  5. Choi JH, Kim SM, Lee GH, Jin SW, Lee HS, Chung YC, Jeong HG (2019) Platyconic acid a, platycodi radix-derived saponin, suppresses TGF-1-induced activation of hepatic stellate cells via blocking SMAD and activating the PPAR signaling pathway. Cells 8. https://doi.org/10.3390/cells8121544

  6. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114:842–845

    Article  CAS  Google Scholar 

  7. de Souza IC, Martins LA, de Vasconcelos M, de Oliveira CM, Barbe-Tuana F, Andrade CB, Pettenuzzo LF, Borojevic R, Margis R, Guaragna R, Guma FC (2015) Resveratrol regulates the quiescence-like induction of activated stellate cells by modulating the PPARgamma/SIRT1 ratio. J Cell Biochem 116:2304–2312. https://doi.org/10.1002/jcb.25181

    Article  CAS  PubMed  Google Scholar 

  8. Dewidar B, Meyer C, Dooley S, Meindl B, Nadja (2019) TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells 8. https://doi.org/10.3390/cells8111419

  9. Diehl AM, Day C (2017) Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med 377:2063–2072. https://doi.org/10.1056/NEJMra1503519

    Article  CAS  PubMed  Google Scholar 

  10. Fabregat I, Caballero-Diaz D (2018) Transforming growth factor-beta-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol 8:357. https://doi.org/10.3389/fonc.2018.00357

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hart KM, Fabre T, Sciurba JC, Gieseck RL, Borthwick LA, Vannella KM, Acciani TH, de Queiroz PR, Thompson RW, White S, Soucy G, Bilodeau M, Ramalingam TR, Arron JR, Shoukry NH, Wynn TA (2017) Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β. Sci Transl Med 9:eaal3694. https://doi.org/10.1126/scitranslmed.aal3694

    Article  CAS  PubMed  Google Scholar 

  12. Hazra S, Xiong S, Wang J, Rippe RA, Krishna V, Chatterjee K, Tsukamoto H (2004) Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem 279:11392–11401

    Article  CAS  Google Scholar 

  13. He J, Bai K, Hong B, Zhang F, Zheng S (2017) Docosahexaenoic acid attenuates carbon tetrachloride-induced hepatic fibrosis in rats. Int Immunopharmacol 53:56–62. https://doi.org/10.1016/j.intimp.2017.09.013

    Article  CAS  PubMed  Google Scholar 

  14. Hellerbrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA (1999) The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo. J Hepatol 30:77–87

    Article  CAS  Google Scholar 

  15. Koyama Y, Brenner DA (2017) Liver inflammation and fibrosis. J Clin Invest 127:55–64. https://doi.org/10.1172/jci88881

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lakshmi SP, Reddy AT, Reddy RC (2017) Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements. Biochem J 474:1531–1546. https://doi.org/10.1042/BCJ20160943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu J, Kong D, Qiu J, Xie Y, Lu Z, Zhou C, Liu X, Zhang R, Wang Y (2019) Praziquantel ameliorates CCl -induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells. Br J Pharmacol 176:4666–4680. https://doi.org/10.1111/bph.14831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu X, Xu J, Rosenthal S, Zhang L-J, McCubbin R, Meshgin N, Shang L, Koyama Y, Ma H-Y, Sharma S, Heinz S, Glass CK, Benner C, Brenner DA, Kisseleva T (2020) Identification of lineage-specific transcription factors that prevent activation of hepatic stellate cells and promote fibrosis resolution. Gastroenterology 158:1728–1744.e14. https://doi.org/10.1053/j.gastro.2020.01.027

    Article  CAS  PubMed  Google Scholar 

  19. Luo W, Xu Q, Wang Q, Wu H, Hua J (2017) Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci Rep 7:44612. https://doi.org/10.1038/srep44612

    Article  PubMed  PubMed Central  Google Scholar 

  20. Luo X, Li H, Ma L, Zhou J, Guo X, Woo SL, Pei Y, Knight LR, Deveau M, Chen Y, Qian X, Xiao X, Li Q, Chen X, Huo Y, McDaniel K, Francis H, Glaser S, Meng F, Alpini G, Wu C (2018) Expression of STING is increased in liver tissues from patients with NAFLD and promotes macrophage-mediated hepatic inflammation and fibrosis in mice. Gastroenterology 155:1971–1984.e1974. https://doi.org/10.1053/j.gastro.2018.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ma L, Zeng Y, Wei J, Yang D, Ding G, Liu J, Shang J, Kang Y, Ji X (2018) Knockdown of LOXL1 inhibits TGF-β1-induced proliferation and fibrogenesis of hepatic stellate cells by inhibition of Smad2/3 phosphorylation. Biomed Pharmacother 107:1728–1735. https://doi.org/10.1016/j.biopha.2018.08.156

    Article  CAS  PubMed  Google Scholar 

  22. Mann DA, Smart DE (2002) Transcriptional regulation of hepatic stellate cell activation. Gut 50:891–896

    Article  CAS  Google Scholar 

  23. Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, Bonacchi A, Caporale R, Laffi G, Pinzani M, Gentilini P (2000) Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119:466–478

    Article  CAS  Google Scholar 

  24. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere J-P, Schwabe RF (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823. https://doi.org/10.1038/ncomms3823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mederacke I, Dapito DH, Affò S, Uchinami H, Schwabe RF (2015) High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers. Nat Protoc 10:305–315. https://doi.org/10.1038/nprot.2015.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Meier RPH, Meyer J, Montanari E, Lacotte S, Balaphas A, Muller YD, Clement S, Negro F, Toso C, Morel P, Buhler LH (2019) Interleukin-1 receptor antagonist modulates liver inflammation and fibrosis in mice in a model-dependent manner. Int J Mol Sci 20. https://doi.org/10.3390/ijms20061295

  27. Morán-Salvador E, Titos E, Rius B, González-Périz A, García-Alonso V, López-Vicario C, Miquel R, Barak Y, Arroyo V, Clària J (2013) Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. J Hepatol 59:1045–1053. https://doi.org/10.1016/j.jhep.2013.06.023

    Article  CAS  PubMed  Google Scholar 

  28. Prestigiacomo V, Weston A, Suter-Dick L (2020) Rat multicellular 3D liver microtissues to explore TGF-beta1 induced effects. J Pharmacol Toxicol Methods 101:106650. https://doi.org/10.1016/j.vascn.2019.106650

    Article  CAS  PubMed  Google Scholar 

  29. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616. https://doi.org/10.1016/j.freeradbiomed.2010.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schuppan D, Surabattula R, Wang XY (2018) Determinants of fibrosis progression and regression in NASH. J Hepatol 68:238–250. https://doi.org/10.1016/j.jhep.2017.11.012

    Article  CAS  Google Scholar 

  31. Schwabe RF, Tabas I, Pajvani UB (2020) Mechanisms of fibrosis development in NASH. Gastroenterology 158:1913–1928. https://doi.org/10.1053/j.gastro.2019.11.311

    Article  CAS  PubMed  Google Scholar 

  32. Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF (2007) TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 13:1324–1332

    Article  CAS  Google Scholar 

  33. Shi Y, Massagué J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700

    Article  CAS  Google Scholar 

  34. Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, Irie R, Takajo T, Wada A, Horiuchi K, Inaba K, Hanawa Y, Shibuya N, Okada Y, Kurihara C, Nishii S, Mizoguchi A, Hozumi H, Watanabe C, Komoto S, Nagao S, Yamamoto J, Miura S, Hokari R, Kanai T (2019) Lipoprotein lipase up-regulation in hepatic stellate cells exacerbates liver fibrosis in nonalcoholic steatohepatitis in mice. Hepatol Commun 3:1098–1112. https://doi.org/10.1002/hep4.1383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836–1846. https://doi.org/10.1002/hep.24001

    Article  CAS  PubMed  Google Scholar 

  36. Tsuchida T, Friedman SL (2017) Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 14:397–411. https://doi.org/10.1038/nrgastro.2017.38

    Article  CAS  PubMed  Google Scholar 

  37. Wu CW, Chu ESH, Lam CNY, Cheng ASL, Lee CW, Wong VWS, Sung JJY, Yu J (2010) PPARgamma is essential for protection against nonalcoholic steatohepatitis. Gene Ther 17:790–798. https://doi.org/10.1038/gt.2010.41

    Article  CAS  PubMed  Google Scholar 

  38. Wu L, Guo C, Wu J (2020) Therapeutic potential of PPARγ natural agonists in liver diseases. J Cell Mol Med 24:2736–2748. https://doi.org/10.1111/jcmm.15028

    Article  PubMed  PubMed Central  Google Scholar 

  39. Xiong X, Kuang H, Ansari S, Liu T, Gong J, Wang S, Zhao XY, Ji Y, Li C, Guo L, Zhou L, Chen Z, Leon-Mimila P, Chung MT, Kurabayashi K, Opp J, Campos-Perez F, Villamil-Ramirez H, Canizales-Quinteros S, Lyons R, Lumeng CN, Zhou B, Qi L, Huertas-Vazquez A, Lusis AJ, Xu XZS, Li S, Yu Y, Li JZ, Lin JD (2019) Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol Cell 75:644–660.e645. https://doi.org/10.1016/j.molcel.2019.07.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xiong X, Kuang H, Liu T, Lin JD (2020) A single-cell perspective of the mammalian liver in health and disease. Hepatology 71:1467–1473. https://doi.org/10.1002/hep.31149

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhao HW, Zhang ZF, Chai X, Li GQ, Cui HR, Wang HB, Meng YK, Liu HM, Wang JB, Li RS, Bai ZF, Xiao XH (2016) Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-beta1 signaling pathways. Int Immunopharmacol 36:249–255. https://doi.org/10.1016/j.intimp.2016.04.040

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (JH, NO. 81770572, NO. 81470842).

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Author notes

  1. Xi-Xi Ni, Xiao-Yun Li and Qi Wang contributed equally to this work.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, People’s Republic of China

    Xi-Xi Ni, Xiao-Yun Li, Qi Wang & Jing Hua

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  1. Xi-Xi Ni
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  2. Xiao-Yun Li
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  3. Qi Wang
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  4. Jing Hua
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Contributions

Ni XX, Li XY, and Wang Q contributed equally to this work, performed the experiments, and analyzed the data; Hua J designed the study; Ni XX and Hua J wrote the paper.

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Correspondence to Jing Hua.

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The authors declare that they have no conflict of interest.

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All animal experiments fulfilled Shanghai Jiao Tong University criteria for the humane treatment of laboratory animals and were approved by the Ren Ji Hospital Animal Care and Use Committee (SYXK 2011-0121).

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Key Points

• HSCs are activated gradually with decreased PPAR-γ expression in the liver from NASH.

• PPAR-γ agonist inhibited HSC activation and reverted their phenotype.

• PPAR-γ agonist alleviated excessive hepatic lipid accumulation and reduced oxidative stress.

• HSC activation and liver fibrosis were reduced by PPAR-γ agonist via TGF-β1/Smad inhibition.

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Ni, XX., Li, XY., Wang, Q. et al. Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-β1/Smad signaling pathway. J Physiol Biochem 77, 35–45 (2021). https://doi.org/10.1007/s13105-020-00777-7

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