FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis
Fibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR‐16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senes...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2022-07-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1909 |
| _version_ | 1797935683166273536 |
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| author | April O’Brien Tianhao Zhou Tori White Abigail Medford Lixian Chen Konstantina Kyritsi Nan Wu Jonathan Childs Danaleigh Stiles Ludovica Ceci Sanjukta Chakraborty Burcin Ekser Leonardo Baiocchi Guido Carpino Eugenio Gaudio Chaodong Wu Lindsey Kennedy Heather Francis Gianfranco Alpini Shannon Glaser |
| author_facet | April O’Brien Tianhao Zhou Tori White Abigail Medford Lixian Chen Konstantina Kyritsi Nan Wu Jonathan Childs Danaleigh Stiles Ludovica Ceci Sanjukta Chakraborty Burcin Ekser Leonardo Baiocchi Guido Carpino Eugenio Gaudio Chaodong Wu Lindsey Kennedy Heather Francis Gianfranco Alpini Shannon Glaser |
| author_sort | April O’Brien |
| collection | DOAJ |
| description | Fibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR‐16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senescence, fibrosis, inflammation, angiogenesis, and its potential interaction with miR‐16, are unknown. In vivo studies were performed in male bile duct–ligated (BDL, 12‐week‐old) mice, multidrug resistance 2 knockout (Mdr2−/−) mice (10‐week‐old), and their corresponding controls, treated with recombinant human FGF1 (rhFGF1), fibroblast growth factor receptor (FGFR) antagonist (AZD4547), or anti‐FGF1 monoclonal antibody (mAb). In vitro, the human cholangiocyte cell line (H69) and human hepatic stellate cells (HSCs) were used to determine the expression of proliferation, fibrosis, angiogenesis, and inflammatory genes following rhFGF1 treatment. PSC patient and control livers were used to evaluate FGF1 and miR‐16 expression. Intrahepatic bile duct mass (IBDM), along with hepatic fibrosis and inflammation, increased in BDL mice treated with rhFGF1, with a corresponding decrease in miR‐16, while treatment with AZD4547 or anti‐FGF1 mAb decreased hepatic fibrosis, IBDM, and inflammation in BDL and Mdr2−/− mice. In vitro, H69 and HSCs treated with rhFGF1 had increased expression of proliferation, fibrosis, and inflammatory markers. PSC samples also showed increased FGF1 and FGFRs with corresponding decreases in miR‐16 compared with healthy controls. Conclusion: Our study demonstrates that suppression of FGF1 and miR‐16 signaling decreases the presence of hepatic fibrosis, biliary proliferation, inflammation, senescence, and angiogenesis. Targeting the FGF1 and miR‐16 axis may provide therapeutic options in treating cholangiopathies such as PSC. |
| first_indexed | 2024-04-10T18:19:05Z |
| format | Article |
| id | doaj.art-69304a63d3f14d1cb6f65abe81d68eed |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-04-10T18:19:05Z |
| publishDate | 2022-07-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-69304a63d3f14d1cb6f65abe81d68eed2023-02-02T07:50:00ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2022-07-01671574158810.1002/hep4.1909FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing CholangitisApril O’Brien0Tianhao Zhou1Tori White2Abigail Medford3Lixian Chen4Konstantina Kyritsi5Nan Wu6Jonathan Childs7Danaleigh Stiles8Ludovica Ceci9Sanjukta Chakraborty10Burcin Ekser11Leonardo Baiocchi12Guido Carpino13Eugenio Gaudio14Chaodong Wu15Lindsey Kennedy16Heather Francis17Gianfranco Alpini18Shannon Glaser19Department of Medical Physiology Texas A&M University College of Medicine Bryan TX USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADepartment of Medical Physiology Texas A&M University College of Medicine Bryan TX USADepartment of Medical Physiology Texas A&M University College of Medicine Bryan TX USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADepartment of Medical Physiology Texas A&M University College of Medicine Bryan TX USADepartment of Medical Physiology Texas A&M University College of Medicine Bryan TX USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADepartment of Medical Physiology Texas A&M University College of Medicine Bryan TX USADivision of Transplant Surgery Department of Surgery Indiana University School of Medicine Indianapolis IN USAHepatology Unit Dept of Medicine University of Tor Vergata Rome Rome ItalyDepartment of Movement Human and Health Sciences, University of Rome “Foro Italico” Rome ItalyDepartment of Anatomical Histological Forensic Medicine and Orthopedics Sciences Sapienza University of Rome Rome ItalyDepartment of Nutrition Texas A&M University College Station TX USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADivision of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis IN USADepartment of Medical Physiology Texas A&M University College of Medicine Bryan TX USAFibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR‐16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senescence, fibrosis, inflammation, angiogenesis, and its potential interaction with miR‐16, are unknown. In vivo studies were performed in male bile duct–ligated (BDL, 12‐week‐old) mice, multidrug resistance 2 knockout (Mdr2−/−) mice (10‐week‐old), and their corresponding controls, treated with recombinant human FGF1 (rhFGF1), fibroblast growth factor receptor (FGFR) antagonist (AZD4547), or anti‐FGF1 monoclonal antibody (mAb). In vitro, the human cholangiocyte cell line (H69) and human hepatic stellate cells (HSCs) were used to determine the expression of proliferation, fibrosis, angiogenesis, and inflammatory genes following rhFGF1 treatment. PSC patient and control livers were used to evaluate FGF1 and miR‐16 expression. Intrahepatic bile duct mass (IBDM), along with hepatic fibrosis and inflammation, increased in BDL mice treated with rhFGF1, with a corresponding decrease in miR‐16, while treatment with AZD4547 or anti‐FGF1 mAb decreased hepatic fibrosis, IBDM, and inflammation in BDL and Mdr2−/− mice. In vitro, H69 and HSCs treated with rhFGF1 had increased expression of proliferation, fibrosis, and inflammatory markers. PSC samples also showed increased FGF1 and FGFRs with corresponding decreases in miR‐16 compared with healthy controls. Conclusion: Our study demonstrates that suppression of FGF1 and miR‐16 signaling decreases the presence of hepatic fibrosis, biliary proliferation, inflammation, senescence, and angiogenesis. Targeting the FGF1 and miR‐16 axis may provide therapeutic options in treating cholangiopathies such as PSC.https://doi.org/10.1002/hep4.1909 |
| spellingShingle | April O’Brien Tianhao Zhou Tori White Abigail Medford Lixian Chen Konstantina Kyritsi Nan Wu Jonathan Childs Danaleigh Stiles Ludovica Ceci Sanjukta Chakraborty Burcin Ekser Leonardo Baiocchi Guido Carpino Eugenio Gaudio Chaodong Wu Lindsey Kennedy Heather Francis Gianfranco Alpini Shannon Glaser FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis Hepatology Communications |
| title | FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis |
| title_full | FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis |
| title_fullStr | FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis |
| title_full_unstemmed | FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis |
| title_short | FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis |
| title_sort | fgf1 signaling modulates biliary injury and liver fibrosis in the mdr2 mouse model of primary sclerosing cholangitis |
| url | https://doi.org/10.1002/hep4.1909 |
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