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Sci Rep. 2017 Mar 3;7:42563. doi: 10.1038/srep42563.

Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells.

Author information

1
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.
2
Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland.
3
Department of Pharmacology, University of Valencia-FISABIO, Valencia, Spain.
4
Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
5
University of Western Australia, West Leederville, WA, Australia.
6
Department of Pathology, University of Illinois at Chicago, Chicago, USA.
7
Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
8
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, USA.
9
Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.

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.

PMID:
28256512
PMCID:
PMC5335661
DOI:
10.1038/srep42563
[Indexed for MEDLINE]
Free PMC Article

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