Yonsei Medical Journal

Yonsei Univ College Medicine (연세대학교의과대학)
권호 표지
DOI QR코드

DOI QR Code

S100A4 Gene is Crucial for Methionine-Choline-Deficient Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice

  • Zhang, Yin-Hua (Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine) ;
  • Ma, De-Qiang (Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine) ;
  • Ding, De-Ping (Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine) ;
  • Li, Juan (Maternal and Child Health-Care Hospital) ;
  • Chen, Lin-Li (Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine) ;
  • Ao, Kang-Jian (Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine) ;
  • Tian, You-You (Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine)
  • Received : 2018.04.18
  • Accepted : 2018.08.24
  • Published : 2018.11.01
⟨ Previous Next ⟩

Abstract

Purpose: To explore the influence of S100 calcium binding protein A4 (S100A4) knockout (KO) on methionine-choline-deficient (MCD) diet-induced non-alcoholic fatty liver disease (NAFLD) in mice. Materials and Methods: S100A4 KO mice (n=20) and their wild-type (WT) counterparts (n=20) were randomly divided into KO/MCD, Ko/methionine-choline-sufficient (MCS), WT/MCD, and WT/MCS groups. After 8 weeks of feeding, blood lipid and liver function-related indexes were measured. HE, Oil Red O, and Masson stainings were used to observe the changes of liver histopathology. Additionally, expressions of S100A4 and proinflammatory and profibrogenic cytokines were detected by qRT-PCR and Western blot, while hepatocyte apoptosis was revealed by TUNEL staining. Results: Serum levels of aminotransferase, aspartate aminotransferase, triglyceride, and total cholesterol in mice were increased after 8-week MCD feeding, and hepatocytes performed varying balloon-like changes with increased inflammatory cell infiltration and collagen fibers; however, these effects were improved in mice of KO/MCD group. Meanwhile, total NAFLD activity scores and fibrosis were lower compared to WT+MCD group. Compared to WT/MCS group, S100A4 expression in liver tissue of WT/MCD group was enhanced. The expression of proinflammatory ($TGF-{\alpha}$, $IL-1{\beta}$, IL-6) and profibrogenic cytokines ($TGF-{\beta}1$, COL1A1, ${\alpha}-SMA$) in MCD-induced NAFLD mice were increased, as well as apoptotic index (AI). For MCD group, the expressions of proinflammatory and profibrogenic cytokines and AI in KO mice were lower than those of WT mice. Conclusion: S100A4 was detected to be upregulated in NAFLD, while S100A4 KO alleviated liver fibrosis and inflammation, in addition to inhibiting hepatocyte apoptosis.

Keywords

References

  1. Arner P, Petrus P, Esteve D, Boulomie A, Naslund E, Thorell A, et al. Screening of potential adipokines identifies S100A4 as a marker of pernicious adipose tissue and insulin resistance. Int J Obes (Lond) 2018 Jan 30 [Epub]. https://doi.org/10.1038/s41366-018-0018-0.
  2. Afonso MB, Rodrigues PM, Simao AL, Castro RE. Circulating microRNAs as potential biomarkers in non-alcoholic fatty liver disease and hepatocellular carcinoma. J Clin Med 2016;5:30. https://doi.org/10.3390/jcm5030030
  3. Nair S. Nonalcoholic Fatty liver disease from the perspective of an internist. Ochsner J 2002;4:92-7.
  4. Patel A, Harrison SA. Hepatitis C virus infection and nonalcoholic steatohepatitis. Gastroenterol Hepatol (N Y) 2012;8:305-12.
  5. Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease. Metabolism 2016;65:1026-37. https://doi.org/10.1016/j.metabol.2015.08.018
  6. Saleh A, Kamel L, Ghali A, Ismail A, El Khayat H. Serum levels of astroglial S100-beta and neuron-specific enolase in hepatic encephalopathy patients. East Mediterr Health J 2007;13:1114-23. https://doi.org/10.26719/2007.13.5.1114
  7. Dempsey BR, Rintala-Dempsey AC, Shaw GS. S100 proteins. In: Choi S, editor. Encyclopedia of signaling molecules. New York (NY): Springer; 2012. p.1711-7.
  8. Mukai K, Miyagi T, Nishio K, Yokoyama Y, Yoshioka T, Saito Y, et al. S100A8 production in CXCR2-expressing CD11b+Gr-1high cells aggravates hepatitis in mice fed a high-fat and high-cholesterol diet. J Immunol 2016;196:395-406. https://doi.org/10.4049/jimmunol.1402709
  9. Liu X, Wang Y, Ming Y, Song Y, Zhang J, Chen X, et al. S100A9: a potential biomarker for the progression of non-alcoholic fatty liver disease and the diagnosis of non-alcoholic steatohepatitis. PLoS One 2015;10:e0127352. https://doi.org/10.1371/journal.pone.0127352
  10. Malashkevich VN, Dulyaninova NG, Ramagopal UA, Liriano MA, Varney KM, Knight D, et al. Phenothiazines inhibit S100A4 function by inducing protein oligomerization. Proc Natl Acad Sci U S A 2010;107:8605-10. https://doi.org/10.1073/pnas.0913660107
  11. Hou S, Tian T, Qi D, Sun K, Yuan Q, Wang Z, et al. S100A4 promotes lung tumor development through ${\beta}$-catenin pathway-mediated autophagy inhibition. Cell Death Dis 2018;9:277. https://doi.org/10.1038/s41419-018-0319-1
  12. Oslejskova L, Grigorian M, Gay S, Neidhart M, Senolt L. The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis 2008;67:1499-504. https://doi.org/10.1136/ard.2007.079905
  13. Cerezo LA, Kuncova K, Mann H, Tomcik M, Zamecnik J, Lukanidin E, et al. The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies. Rheumatology (Oxford) 2011;50:1766-72. https://doi.org/10.1093/rheumatology/ker218
  14. Louka ML, Ramzy MM. Involvement of fibroblast-specific protein 1 (S100A4) and matrix metalloproteinase-13 (MMP-13) in CCl4-induced reversible liver fibrosis. Gene 2016;579:29-33. https://doi.org/10.1016/j.gene.2015.12.042
  15. Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013;10:627-36. https://doi.org/10.1038/nrgastro.2013.149
  16. Okubo H, Kushiyama A, Sakoda H, Nakatsu Y, Iizuka M, Taki N, et al. Involvement of resistin-like molecule ${\beta}$ in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice. Sci Rep 2016;6:20157. https://doi.org/10.1038/srep20157
  17. Rizki G, Arnaboldi L, Gabrielli B, Yan J, Lee GS, Ng RK, et al. Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1. J Lipid Res 2006;47:2280-90. https://doi.org/10.1194/jlr.M600198-JLR200
  18. Rinella ME, Elias MS, Smolak RR, Fu T, Borensztajn J, Green RM. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 2008;49:1068-76. https://doi.org/10.1194/jlr.M800042-JLR200
  19. Wang Y, Li J, Zhuge L, Su D, Yang M, Tao S, et al. Comparison between the efficacies of curcumin and puerarin in C57BL/6 mice with steatohepatitis induced by a methionine- and choline-deficient diet. Exp Ther Med 2014;7:663-8. https://doi.org/10.3892/etm.2013.1461
  20. Kim SB, Kang OH, Lee YS, Han SH, Ahn YS, Cha SW, et al. Hepatoprotective effect and synergism of bisdemethoycurcumin against MCD diet-induced nonalcoholic fatty liver disease in mice. PLoS One 2016;11:e0147745. https://doi.org/10.1371/journal.pone.0147745
  21. National Research Council. Guide for the care and use of laboratory animals. 8th ed. Washington (DC): National Academies Press; 2011.
  22. EL Naaman C, Grum-Schwensen B, Mansouri A, Grigorian M, Santoni-Rugiu E, Hansen T, et al. Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene. Oncogene 2004;23:3670-80. https://doi.org/10.1038/sj.onc.1207420
  23. Alam S, Alam M, Alam SMNE, Chowdhury ZR, Kabir J. Prevalence and predictor of nonalcoholic steatohepatitis (NASH) in nonalcoholic fatty liver disease (NAFLD). J Bangladesh Coll Phys Surg 2014;32:71-7.
  24. Garcia-Galiano D, Sanchez-Garrido MA, Espejo I, Montero JL, Costan G, Marchal T, et al. IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients. Obes Surg 2007;17:493-503. https://doi.org/10.1007/s11695-007-9087-1
  25. Ying LI, Hong ZF. Hypothesis of “two hits” in NAFLD. Medical Recapitulate 2013;19:594-6.
  26. Abu El-Asrar AM, Nawaz MI, De Hertogh G, Alam K, Siddiquei MM, Van den Eynde K, et al. S100A4 is upregulated in proliferative diabetic retinopathy and correlates with markers of angiogenesis and fibrogenesis. Mol Vis 2014;20:1209-24.
  27. Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Tsutsumi M. Toxic AGE (TAGE) theory for the pathophysiology of the onset/progression of NAFLD and ALD. Nutrients 2017;9:634. https://doi.org/10.3390/nu9060634
  28. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010;52:1836-46. https://doi.org/10.1002/hep.24001
  29. Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol 2014;7:221-39.
  30. Klingelhofer J, Senolt L, Baslund B, Nielsen GH, Skibshoj I, Pavelka K, et al. Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 2007;56:779-89. https://doi.org/10.1002/art.22398
  31. Tilg H, Moschen AR, Szabo G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2016;64:955-65. https://doi.org/10.1002/hep.28456
  32. Sharifnia T, Antoun J, Verriere TG, Suarez G, Wattacheril J, Wilson KT, et al. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 2015;309:G270-8. https://doi.org/10.1152/ajpgi.00304.2014
  33. Chen L, Li J, Zhang J, Dai C, Liu X, Wang J, et al. S100A4 promotes liver fibrosis via activation of hepatic stellate cells. J Hepatol 2015;62:156-64. https://doi.org/10.1016/j.jhep.2014.07.035
  34. Yan LB, Zhang QB, Zhu X, He M, Tang H. Serum S100 calcium binding protein A4 improves the diagnostic accuracy of transient elastography for assessing liver fibrosis in hepatitis B. Clin Res Hepatol Gastroenterol 2018;42:64-71. https://doi.org/10.1016/j.clinre.2017.05.013
  35. Schneider M, Hansen JL, Sheikh SP. S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases? J Mol Med (Berl) 2008;86:507-22. https://doi.org/10.1007/s00109-007-0301-3
  36. Syn WK, Jung Y, Omenetti A, Abdelmalek M, Guy CD, Yang L, et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 2009;137:1478-88.e8. https://doi.org/10.1053/j.gastro.2009.06.051
  37. Maher JJ. Pathogenesis of NAFLD and NASH. In: Chalasani N, Szabo G, editors. Alcoholic and non-alcoholic fatty liver disease. Cham: Springer; 2016. p.71-101.
  38. Mazzucchelli L. Protein S100A4: too long overlooked by pathologists? Am J Pathol 2002;160:7-13. https://doi.org/10.1016/S0002-9440(10)64342-8
  39. Tomita K, Teratani T, Suzuki T, Oshikawa T, Yokoyama H, Shimamura K, et al. p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. J Hepatol 2012;57:837-43. https://doi.org/10.1016/j.jhep.2012.05.013
  40. Orre LM, Panizza E, Kaminskyy VO, Vernet E, Graslund T, Zhivotovsky B, et al. S100A4 interacts with p53 in the nucleus and promotes p53 degradation. Oncogene 2013;32:5531-40. https://doi.org/10.1038/onc.2013.213