Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells
Por:
Hicks DF, Goossens N, Blas-García A, Tsuchida T, Wooden B, Wallace MC, Nieto N, Lade A, Redhead B, Cederbaum AI, Dudley JT, Fuchs BC, Lee YA, Hoshida Y and Friedman SL
Publicada:
3 mar 2017
Categoría:
Multidisciplinary
Resumen:
We have used a computational approach to identify anti-fibrotic therapies by querying a transcriptome. A transcriptome signature of activated hepatic stellate cells (HSCs), the primary collagen-secreting cell in liver, and queried against a transcriptomic database that quantifies changes in gene expression in response to 1,309 FDA-approved drugs and bioactives (CMap). The flavonoid apigenin was among 9 top-ranked compounds predicted to have anti-fibrotic activity; indeed, apigenin dose-dependently reduced collagen I in the human HSC line, TWNT-4. To identify proteins mediating apigenin's effect, we next overlapped a 122-gene signature unique to HSCs with a list of 160 genes encoding proteins that are known to interact with apigenin, which identified C1QTNF2, encoding for Complement C1q tumor necrosis factor-related protein 2, a secreted adipocytokine with metabolic effects in liver. To validate its disease relevance, C1QTNF2 expression is reduced during hepatic stellate cell activation in culture and in a mouse model of alcoholic liver injury in vivo, and its expression correlates with better clinical outcomes in patients with hepatitis C cirrhosis (n = 216), suggesting it may have a protective role in cirrhosis progression. These findings reinforce the value of computational approaches to drug discovery for hepatic fibrosis, and identify C1QTNF2 as a potential mediator of apigenin's anti-fibrotic activity.
Filiaciones:
Hicks DF:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Goossens N:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Department of Pharmacology, University of Valencia-FISABIO, Valencia, Spain
Tsuchida T:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan
Wooden B:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Wallace MC:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
University of Western Australia, West Leederville, WA, Australia
Nieto N:
Department of Pathology, University of Illinois at Chicago, Chicago, USA
Lade A:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Redhead B:
Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Cederbaum AI:
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, USA
Dudley JT:
Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Fuchs BC:
Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA
Lee YA:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Hoshida Y:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Friedman SL:
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
gold, Green Published
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