Startseite A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency

  • Evelyn Yip , Aminah Giousoh , Connie Fung , Brendan Wilding , Monica D. Prakash , Caitlin Williams , Heather Verkade , Robert J. Bryson-Richardson und Phillip I. Bird EMAIL logo
Veröffentlicht/Copyright: 15. Mai 2019
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 400 Heft 12

Abstract

In human α1-antitrypsin deficiency, homozygous carriers of the Z (E324K) mutation in the gene SERPINA1 have insufficient circulating α1-antitrypsin and are predisposed to emphysema. Misfolding and accumulation of the mutant protein in hepatocytes also causes endoplasmic reticulum stress and underpins long-term liver damage. Here, we describe transgenic zebrafish (Danio rerio) expressing the wildtype or the Z mutant form of human α1-antitrypsin in hepatocytes. As observed in afflicted humans, and in rodent models, about 80% less α1-antitrypsin is evident in the circulation of zebrafish expressing the Z mutant. Although these zebrafish also show signs of liver stress, they do not accumulate α1-antitrypsin in hepatocytes. This new zebrafish model will provide useful insights into understanding and treatment of α1-antitrypsin deficiency.

Keywords: α1-antitrypsin deficiency; Danio rerio; liver; serpin; SERPINA1

Acknowledgements

This work was funded by the Alpha-1 Foundation (USA) and the National Health and Medical Research Council (Australia). We thank Dr Mark Brantly (University of Florida) and the Alpha-1 Foundation for providing human tissue samples from the Foundation’s DNA and Tissue Bank. We also thank Dr Richard Sifers (Baylor College of Medicine) for antitrypsin expression plasmids; Dr David Lomas (University College London) for the monoclonal antibody 2C1; and Dr Julio Coll (National Institute for Agricultural and Food Research and Technology Madrid) for the anti-IgM antibody. We are grateful to the staff of the Monash FishCore facility for zebrafish care and maintenance, and for the input of Dr Stephen Bottomley in the early stages of the project.

References

Ali, R., Perfumo, S., della Rocca, C., Amicone, L., Pozzi, L., McCullagh, P., Millward-Sadler, H., Edwards, Y., Povey, S., and Tripodi, M. (1994). Evaluation of a transgenic mouse model for α-1-antitrypsin (AAT) related liver disease. Ann. Hum. Genet. 58, 305–320.10.1111/j.1469-1809.1994.tb00728.xSuche in Google Scholar PubMed

Balciunas, D., Wangensteen, K.J., Wilber, A., Bell, J., Geurts, A., Sivasubbu, S., Wang, X., Hackett, P.B., Largaespada, D.A., McIvor, R.S., et al. (2006). Harnessing a high cargo-capacity transposon for genetic applications in vertebrates. PLoS Genet. 2, e169.10.1371/journal.pgen.0020169Suche in Google Scholar PubMed PubMed Central

Borel, F., Sun, H., Zieger, M., Cox, A., Cardozo, B., Li, W., Oliveira, G., Davis, A., Gruntman, A., Flotte, T.R., et al. (2018). Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Proc. Natl. Acad. Sci. USA 115, 2788–2793.10.1073/pnas.1713689115Suche in Google Scholar PubMed PubMed Central

Carlson, J.A., Rogers, B.B., Sifers, R.N., Finegold, M.J., Clift, S.M., DeMayo, F.J., Bullock, D.W., and Woo, S.L. (1989). Accumulation of PiZ α1-antitrypsin causes liver damage in transgenic mice. J. Clin. Invest. 83, 1183–1190.10.1172/JCI113999Suche in Google Scholar PubMed PubMed Central

Carrell, R.W. and Lomas, D.A. (2002). Alpha1-antitrypsin deficiency – a model for conformational diseases. N. Engl. J. Med. 346, 45–53.10.1056/NEJMra010772Suche in Google Scholar PubMed

Cheng, W., Guo, L., Zhang, Z., Soo, H.M., Wen, C., Wu, W., and Peng, J. (2006). HNF factors form a network to regulate liver-enriched genes in zebrafish. Dev. Biol. 294, 482–496.10.1016/j.ydbio.2006.03.018Suche in Google Scholar PubMed

Chinchilla, B., Gomez-Casado, E., Encinas, P., Falco, A., Estepa, A., and Coll, J. (2013). In vitro neutralization of viral hemorrhagic septicemia virus by plasma from immunized zebrafish. Zebrafish 10, 43–51.10.1089/zeb.2012.0805Suche in Google Scholar PubMed

de Serres, F.J. and Blanco, I. (2012). Prevalence of alpha1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review. Ther. Adv. Respir. Dis. 6, 277–295.10.1177/1753465812457113Suche in Google Scholar PubMed

Distel, M., Wullimann, M.F., and Koster, R.W. (2009). Optimized Gal4 genetics for permanent gene expression mapping in zebrafish. Proc. Natl. Acad. Sci. USA 106, 13365–13370.10.1073/pnas.0903060106Suche in Google Scholar PubMed PubMed Central

Dycaico, M.J., Grant, S.G., Felts, K., Nichols, W.S., Geller, S.A., Hager, J.H., Pollard, A.J., Kohler, S.W., Short, H.P., Jirik, F.R., et al. (1988). Neonatal hepatitis induced by α1-antitrypsin: a transgenic mouse model. Science 242, 1409–1412.10.1126/science.3264419Suche in Google Scholar PubMed

Ekeowa, U.I., Gooptu, B., Belorgey, D., Hagglof, P., Karlsson-Li, S., Miranda, E., Perez, J., MacLeod, I., Kroger, H., Marciniak, S.J., et al. (2009). α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies. Clin. Sci. (Lond). 116, 837–850.10.1042/CS20080484Suche in Google Scholar

Eriksson, S., Carlson, J., and Velez, R. (1986). Risk of cirrhosis and primary liver cancer in α1-antitrypsin deficiency. N. Engl. J. Med. 314, 736–739.10.1056/NEJM198603203141202Suche in Google Scholar

Geller, S.A., Nichols, W.S., Dycaico, M.J., Felts, K.A., and Sorge, J.A. (1990). Histopathology of α1-antitrypsin liver disease in a transgenic mouse model. Hepatology 12, 40–47.10.1002/hep.1840120108Suche in Google Scholar

Geller, S.A., Nichols, W.S., Kim, S., Tolmachoff, T., Lee, S., Dycaico, M.J., Felts, K., and Sorge, J.A. (1994). Hepatocarcinogenesis is the sequel to hepatitis in Z#2 α1-antitrypsin transgenic mice: histopathological and DNA ploidy studies. Hepatology 19, 389–397.10.1002/hep.1840190218Suche in Google Scholar

Ghishan, F.K., Gray, G.F., and Greene, H.L. (1983). α1-Antitrypsin deficiency presenting with ascites and cirrhosis in the neonatal period. Gastroenterology 85, 435–438.10.1016/0016-5085(83)90335-9Suche in Google Scholar

Giovannoni, I., Callea, F., Stefanelli, M., Mariani, R., Santorelli, F.M., and Francalanci, P. (2015). Alpha-1-antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human. Liver Int. 35, 198–206.10.1111/liv.12504Suche in Google Scholar PubMed

Goessling, W. and Sadler, K.C. (2015). Zebrafish: an important tool for liver disease research. Gastroenterology 149, 1361–1377.10.1053/j.gastro.2015.08.034Suche in Google Scholar PubMed PubMed Central

Gooptu, B. and Lomas, D.A. (2009). Conformational pathology of the serpins: themes, variations, and therapeutic strategies. Annu. Rev. Biochem. 78, 147–176.10.1146/annurev.biochem.78.082107.133320Suche in Google Scholar PubMed

Gooptu, B., Ekeowa, U.I., and Lomas, D.A. (2009). Mechanisms of emphysema in α1-antitrypsin deficiency: molecular and cellular insights. Eur. Respir. J. 34, 475–488.10.1183/09031936.00096508Suche in Google Scholar PubMed

Granell, S., Baldini, G., Mohammad, S., Nicolin, V., Narducci, P., Storrie, B., and Baldini, G. (2008). Sequestration of mutated α1-antitrypsin into inclusion bodies is a cell-protective mechanism to maintain endoplasmic reticulum function. Mol. Biol. Cell 19, 572–586.10.1091/mbc.e07-06-0587Suche in Google Scholar PubMed PubMed Central

Her, G.M., Chiang, C.C., Chen, W.Y., and Wu, J.L. (2003). In vivo studies of liver-type fatty acid binding protein (L-FABP) gene expression in liver of transgenic zebrafish (Danio rerio). FEBS Lett 538, 125–133.10.1016/S0014-5793(03)00157-1Suche in Google Scholar

Howarth, D.L., Passeri, M., and Sadler, K.C. (2011). Drinks like a fish: using zebrafish to understand alcoholic liver disease. Alcohol Clin. Exp. Res. 35, 826–829.10.1111/j.1530-0277.2010.01407.xSuche in Google Scholar PubMed PubMed Central

Huang, C.J., Tu, C.T., Hsiao, C.D., Hsieh, F.J., and Tsai, H.J. (2003). Germ-line transmission of a myocardium-specific GFP transgene reveals critical regulatory elements in the cardiac myosin light chain 2 promoter of zebrafish. Dev. Dyn. 228, 30–40.10.1002/dvdy.10356Suche in Google Scholar PubMed

Hubner, R.H., Leopold, P.L., Kiuru, M., De, B.P., Krause, A., and Crystal, R.G. (2009). Dysfunctional glycogen storage in a mouse model of α1-antitrypsin deficiency. Am. J. Respir. Cell Mol. Biol. 40, 239–247.10.1165/rcmb.2008-0029OCSuche in Google Scholar PubMed PubMed Central

Kamimoto, T., Shoji, S., Hidvegi, T., Mizushima, N., Umebayashi, K., Perlmutter, D.H., and Yoshimori, T. (2006). Intracellular inclusions containing mutant α1-antitrypsin Z are propagated in the absence of autophagic activity. J. Biol. Chem. 281, 4467–4476.10.1074/jbc.M509409200Suche in Google Scholar PubMed

Kim, J.H., Lee, S.R., Li, L.H., Park, H.J., Park, J.H., Lee, K.Y., Kim, M.K., Shin, B.A., and Choi, S.Y. (2011). High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One 6, e18556.10.1371/journal.pone.0018556Suche in Google Scholar PubMed PubMed Central

Kwan, K.M., Fujimoto, E., Grabher, C., Mangum, B.D., Hardy, M.E., Campbell, D.S., Parant, J.M., Yost, H.J., Kanki, J.P., and Chien, C.B. (2007). The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs. Dev. Dyn. 236, 3088–3099.10.1002/dvdy.21343Suche in Google Scholar PubMed

Lomas, D.A., Evans, D.L., Finch, J.T., and Carrell, R.W. (1992). The mechanism of Z α1-antitrypsin accumulation in the liver. Nature 357, 605–607.10.1038/357605a0Suche in Google Scholar PubMed

Marcus, N.Y., Brunt, E.M., Blomenkamp, K., Ali, F., Rudnick, D.A., Ahmad, M., and Teckman, J.H. (2010). Characteristics of hepatocellular carcinoma in a murine model of α1-antitrypsin deficiency. Hepatol. Res. 40, 641–653.10.1111/j.1872-034X.2010.00663.xSuche in Google Scholar PubMed PubMed Central

Miranda, E. and Lomas, D.A. (2006). Neuroserpin: a serpin to think about. Cell Mol. Life Sci. 63, 709–722.10.1007/s00018-005-5077-4Suche in Google Scholar PubMed

Miranda, E., Perez, J., Ekeowa, U.I., Hadzic, N., Kalsheker, N., Gooptu, B., Portmann, B., Belorgey, D., Hill, M., Chambers, S., et al. (2010). A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency. Hepatology 52, 1078–1088.10.1002/hep.23760Suche in Google Scholar

Mitchell, E.L. and Khan, Z. (2017). Liver disease in α1 antitrypsin deficiency: current approaches and future directions. Curr. Pathobiol. Rep. 5, 243–252.10.1007/s40139-017-0147-5Suche in Google Scholar

Nelson, D.R., Teckman, J., Di Bisceglie, A.M., and Brenner, D.A. (2012). Diagnosis and management of patients with α1-antitrypsin (A1AT) deficiency. Clin. Gastroenterol. Hepatol. 10, 575–580.10.1016/j.cgh.2011.12.028Suche in Google Scholar

Pan, S., Huang, L., McPherson, J., Muzny, D., Rouhani, F., Brantly, M., Gibbs, R., and Sifers, R.N. (2009). Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in α1-antitrypsin deficiency. Hepatology 50, 275–281.10.1002/hep.22974Suche in Google Scholar

Rudnick, D.A., Liao, Y., An, J.K., Muglia, L.J., Perlmutter, D.H., and Teckman, J.H. (2004). Analyses of hepatocellular proliferation in a mouse model of α1-antitrypsin deficiency. Hepatology 39, 1048–1055.10.1002/hep.20118Suche in Google Scholar

Sano, R. and Reed, J.C. (2013). ER stress-induced cell death mechanisms. Biochim. Biophys. Acta. 1833, 3460–3470.10.1016/j.bbamcr.2013.06.028Suche in Google Scholar

Sifers, R.N., Carlson, J.A., Clift, S.M., DeMayo, F.J., Bullock, D.W., and Woo, S.L. (1987). Tissue specific expression of the human α1-antitrypsin gene in transgenic mice. Nucleic Acids Res. 15, 1459–1475.10.1093/nar/15.4.1459Suche in Google Scholar

Sifers, R.N., Hardick, C.P., and Woo, S.L. (1989). Disruption of the 290–342 salt bridge is not responsible for the secretory defect of the PiZ α1-antitrypsin variant. J. Biol. Chem. 264, 2997–3001.10.1016/S0021-9258(19)81712-XSuche in Google Scholar

Teckman, J.H. (2013). Liver disease in α1 antitrypsin deficiency: current understanding and future therapy. COPD 10 (Suppl 1), 35–43.10.3109/15412555.2013.765839Suche in Google Scholar PubMed

Teckman, J.H., An, J.K., Loethen, S., and Perlmutter, D.H. (2002). Fasting in α1-antitrypsin deficient liver: constitutive [correction of consultative] activation of autophagy. Am. J. Physiol. Gastrointest. Liver. Physiol. 283, G1156–1165.10.1152/ajpgi.00041.2002Suche in Google Scholar PubMed

Topic, A., Ljujic, M., and Radojkovic, D. (2012). Alpha-1-antitrypsin in pathogenesis of hepatocellular carcinoma. Hepat. Mon. 12, e7042.10.5812/hepatmon.7042Suche in Google Scholar PubMed PubMed Central

Wang, Y. and Perlmutter, D.H. (2014). Targeting intracellular degradation pathways for treatment of liver disease caused by α1-antitrypsin deficiency. Pediatr. Res. 75, 133–139.10.1038/pr.2013.190Suche in Google Scholar PubMed PubMed Central

Westerfield, M. (2007). The Zebrafish Book, 5th Edition; A guide for the laboratory use of zebrafish (Danio rerio) (Eugene, USA: University of Oregon Press).Suche in Google Scholar

Wu, Y., Swulius, M.T., Moremen, K.W., and Sifers, R.N. (2003).Elucidation of the molecular logic by which misfolded α1-antitrypsin is preferentially selected for degradation. Proc. Natl. Acad. Sci. USA 100, 8229–8234.10.1073/pnas.1430537100Suche in Google Scholar PubMed PubMed Central

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0391).

Received: 2018-10-03
Accepted: 2019-05-06
Published Online: 2019-05-15
Published in Print: 2019-12-18

©2019 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Review
  3. Recent advances in the development of legumain-selective chemical probes and peptide prodrugs
  4. Genes and Nucleic Acids
  5. Research Articles/Short Communications
  6. Tauroursodeoxycholate protects from glycochenodeoxycholate-induced gene expression changes in perfused rat liver
  7. Protein Structure and Function
  8. Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase
  9. Assessment of the denaturation of collagen protein concentrates using different techniques
  10. Membranes, Lipids, Glycobiology
  11. Red blood cells participate in reverse cholesterol transport by mediating cholesterol efflux of high-density lipoprotein and apolipoprotein A-I from THP-1 macrophages
  12. Molecular Medicine
  13. A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency
  14. Cell Biology and Signaling
  15. Geranylgeranyl diphosphate synthase deficiency aggravates lung fibrosis in mice by modulating TGF-β1/BMP-4 signaling
  16. Proteolysis
  17. The lysosomal aminopeptidase tripeptidyl peptidase 1 displays increased activity in malignant pancreatic cysts
https://doi.org/10.1515/hsz-2018-0391
Schlagwörter für diesen Artikel
α1-antitrypsin deficiency; Danio rerio; liver; serpin; SERPINA1

Artikel in diesem Heft

  1. Frontmatter
  2. Review
  3. Recent advances in the development of legumain-selective chemical probes and peptide prodrugs
  4. Genes and Nucleic Acids
  5. Research Articles/Short Communications
  6. Tauroursodeoxycholate protects from glycochenodeoxycholate-induced gene expression changes in perfused rat liver
  7. Protein Structure and Function
  8. Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase
  9. Assessment of the denaturation of collagen protein concentrates using different techniques
  10. Membranes, Lipids, Glycobiology
  11. Red blood cells participate in reverse cholesterol transport by mediating cholesterol efflux of high-density lipoprotein and apolipoprotein A-I from THP-1 macrophages
  12. Molecular Medicine
  13. A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency
  14. Cell Biology and Signaling
  15. Geranylgeranyl diphosphate synthase deficiency aggravates lung fibrosis in mice by modulating TGF-β1/BMP-4 signaling
  16. Proteolysis
  17. The lysosomal aminopeptidase tripeptidyl peptidase 1 displays increased activity in malignant pancreatic cysts
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 27.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2018-0391/html
Button zum nach oben scrollen