A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummary
Background & Aims: Nonalcoholic fatty liver disease is a frequent cause of hepatic dysfunction and is now a global epidemic. This ailment can progress to an advanced form called nonalcoholic steatohepatitis (NASH) and end-stage liver disease. Currently, the molecular basis of NASH pathogenes...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21002216 |
| _version_ | 1819284059349581824 |
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| author | Jihong Ma Xinping Tan Yongkook Kwon Evan R. Delgado Arman Zarnegar Marie C. DeFrances Andrew W. Duncan Reza Zarnegar |
| author_facet | Jihong Ma Xinping Tan Yongkook Kwon Evan R. Delgado Arman Zarnegar Marie C. DeFrances Andrew W. Duncan Reza Zarnegar |
| author_sort | Jihong Ma |
| collection | DOAJ |
| description | Background & Aims: Nonalcoholic fatty liver disease is a frequent cause of hepatic dysfunction and is now a global epidemic. This ailment can progress to an advanced form called nonalcoholic steatohepatitis (NASH) and end-stage liver disease. Currently, the molecular basis of NASH pathogenesis is poorly understood, and no effective therapies exist to treat NASH. These shortcomings are due to the paucity of experimental NASH models directly relevant to humans. Methods: We used chimeric mice with humanized liver to investigate nonalcoholic fatty liver disease in a relevant model. We carried out histologic, biochemical, and molecular approaches including RNA-Seq. For comparison, we used side-by-side human NASH samples. Results: Herein, we describe a “humanized” model of NASH using transplantation of human hepatocytes into fumarylacetoacetate hydrolase-deficient mice. Once fed a high-fat diet, these mice develop NAFLD faithfully, recapitulating human NASH at the histologic, cellular, biochemical, and molecular levels. Our RNA-Seq analyses uncovered that a variety of important signaling pathways that govern liver homeostasis are profoundly deregulated in both humanized and human NASH livers. Notably, we made the novel discovery that hepatocyte growth factor (HGF) function is compromised in human and humanized NASH at several levels including a significant increase in the expression of the HGF antagonists known as NK1/NK2 and marked decrease in HGF activator. Based on these observations, we generated a potent, human-specific, and stable agonist of human MET that we have named META4 (Metaphor) and used it in the humanized NASH model to restore HGF function. Conclusions: Our studies revealed that the humanized NASH model recapitulates human NASH and uncovered that HGF-MET function is impaired in this disease. We show that restoring HGF-MET function by META4 therapy ameliorates NASH and reinstates normal liver function in the humanized NASH model. Our results show that the HGF-MET signaling pathway is a dominant regulator of hepatic homeostasis. |
| first_indexed | 2024-12-24T01:41:21Z |
| format | Article |
| id | doaj.art-7e58c9b02e0346ed9b58c9790204be6a |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-24T01:41:21Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-7e58c9b02e0346ed9b58c9790204be6a2022-12-21T17:21:59ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-01132565582A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummaryJihong Ma0Xinping Tan1Yongkook Kwon2Evan R. Delgado3Arman Zarnegar4Marie C. DeFrances5Andrew W. Duncan6Reza Zarnegar7The Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261The Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261The Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261The Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261; Pittsburgh Liver Research Center, School of Medicine, Pittsburgh, Pennsylvania; McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PennsylvaniaThe Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261The Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261; Pittsburgh Liver Research Center, School of Medicine, Pittsburgh, Pennsylvania; McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PennsylvaniaThe Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261; Pittsburgh Liver Research Center, School of Medicine, Pittsburgh, Pennsylvania; McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PennsylvaniaThe Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261; Pittsburgh Liver Research Center, School of Medicine, Pittsburgh, Pennsylvania; McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Correspondence Address correspondence to: Prof Reza Zarnegar, University of Pittsburgh, Department of Pathology, 200 Lothrop St, Pittsburgh, Pennsylvania 15261. tel: (412) 648-8657; fax: (412) 648-1916.Background & Aims: Nonalcoholic fatty liver disease is a frequent cause of hepatic dysfunction and is now a global epidemic. This ailment can progress to an advanced form called nonalcoholic steatohepatitis (NASH) and end-stage liver disease. Currently, the molecular basis of NASH pathogenesis is poorly understood, and no effective therapies exist to treat NASH. These shortcomings are due to the paucity of experimental NASH models directly relevant to humans. Methods: We used chimeric mice with humanized liver to investigate nonalcoholic fatty liver disease in a relevant model. We carried out histologic, biochemical, and molecular approaches including RNA-Seq. For comparison, we used side-by-side human NASH samples. Results: Herein, we describe a “humanized” model of NASH using transplantation of human hepatocytes into fumarylacetoacetate hydrolase-deficient mice. Once fed a high-fat diet, these mice develop NAFLD faithfully, recapitulating human NASH at the histologic, cellular, biochemical, and molecular levels. Our RNA-Seq analyses uncovered that a variety of important signaling pathways that govern liver homeostasis are profoundly deregulated in both humanized and human NASH livers. Notably, we made the novel discovery that hepatocyte growth factor (HGF) function is compromised in human and humanized NASH at several levels including a significant increase in the expression of the HGF antagonists known as NK1/NK2 and marked decrease in HGF activator. Based on these observations, we generated a potent, human-specific, and stable agonist of human MET that we have named META4 (Metaphor) and used it in the humanized NASH model to restore HGF function. Conclusions: Our studies revealed that the humanized NASH model recapitulates human NASH and uncovered that HGF-MET function is impaired in this disease. We show that restoring HGF-MET function by META4 therapy ameliorates NASH and reinstates normal liver function in the humanized NASH model. Our results show that the HGF-MET signaling pathway is a dominant regulator of hepatic homeostasis.http://www.sciencedirect.com/science/article/pii/S2352345X21002216FAH MiceFatty Liver DiseaseHepatocyte Growth FactorHGFHGF antagonistHigh-fat Diet |
| spellingShingle | Jihong Ma Xinping Tan Yongkook Kwon Evan R. Delgado Arman Zarnegar Marie C. DeFrances Andrew W. Duncan Reza Zarnegar A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummary Cellular and Molecular Gastroenterology and Hepatology FAH Mice Fatty Liver Disease Hepatocyte Growth Factor HGF HGF antagonist High-fat Diet |
| title | A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummary |
| title_full | A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummary |
| title_fullStr | A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummary |
| title_full_unstemmed | A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummary |
| title_short | A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of METSummary |
| title_sort | novel humanized model of nash and its treatment with meta4 a potent agonist of metsummary |
| topic | FAH Mice Fatty Liver Disease Hepatocyte Growth Factor HGF HGF antagonist High-fat Diet |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21002216 |
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