A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of MET
| Autor: | Andrew W. Duncan, Yong-Kook Kwon, Arman Zarnegar, Xinping Tan, Marie C. DeFrances, Evan R. Delgado, Jihong Ma, Reza Zarnegar |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
HFD
high-fat diet HGF antagonist uPA urokinase type plasminogen activator NK2 RC799-869 NK1 Pathogenesis Liver disease Mice RD regular diet PCR polymerase chain reaction Non-alcoholic Fatty Liver Disease Nonalcoholic fatty liver disease HGF Original Research Metabolic Syndrome Hepatocyte Growth Factor FAH fumarylacetoacetate hydrolase Humanized Liver Gastroenterology NASH Diseases of the digestive system. Gastroenterology Type 2 Diabetes PAI-1 plasminogen activator inhibitor-1 MET Hepatocyte growth factor Signal transduction Liver cancer NASH nonalcoholic steatohepatitis medicine.drug Liver Cancer FAH Mice Diet High-Fat Fatty Liver Disease digestive system HGFAC HGF activator NAFLD NTBC 2-(2-nitro-4-trifluoromethylbenzoyl)-1 3-cyclohexanedione medicine Animals tPA tissue type plasminogen activator High-fat Diet Hepatology business.industry nutritional and metabolic diseases medicine.disease digestive system diseases Transplantation Cancer research Hepatocytes HGF hepatocyte growth factor NAFLD nonalcoholic fatty liver disease Metabolic syndrome business |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 2, Pp 565-582 (2022) |
| ISSN: | 2352-345X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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