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National Institute of Environmental Health Sciences

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Publication Detail

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

Authors: Hicks, Daniel F; Goossens, Nicolas; Blas-García, Ana; Tsuchida, Takuma; Wooden, Benjamin; Wallace, Michael C; Nieto, Natalia; Lade, Abigale; Redhead, Benjamin; Cederbaum, Arthur I; Dudley, Joel T; Fuchs, Bryan C; Lee, Youngmin A; Hoshida, Yujin; Friedman, Scott L

Published In Sci Rep, (2017 Mar 03)

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.

PubMed ID: 28256512 Exiting the NIEHS site

MeSH Terms: Animals; Antifibrinolytic Agents/pharmacology*; Apigenin/pharmacology*; Biomarkers; Cell Line; Drug Discovery*; Drug Repositioning*; Hepatic Stellate Cells/drug effects*; Hepatic Stellate Cells/metabolism*; Humans; Mice; Transcriptome*

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