title: Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hicks
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goossens
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Blas-García
authors.affiliation: 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.
authors.forename: Takuma
authors.initials: T
authors.lastname: Tsuchida
authors.affiliation: 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.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wooden
authors.affiliation: 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.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wallace
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Nieto
authors.affiliation: 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.
authors.forename: Abigale
authors.initials: A
authors.lastname: Lade
authors.affiliation: Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Redhead
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Cederbaum
authors.affiliation: Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
authors.affiliation: 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.
authors.forename: Youngmin A
authors.initials: YA
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.affiliation: 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.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology*; D015415:Biomarkers; D002460:Cell Line; D055808:Drug Discovery; D058492:Drug Repositioning; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D059467:Transcriptome
chemical_list: D000933:Antifibrinolytic Agents; D015415:Biomarkers; D047310:Apigenin