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

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

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

Note: Order does not necessarily reflect citation order of authors.

Citation: Hicks, D. F., N. Goossens, A. Blas-García, T. Tsuchida, B. Wooden, M. C. Wallace, N. Nieto, et al. 2017. “Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells.” Scientific Reports 7 (1): 42563. doi:10.1038/srep42563. http://dx.doi.org/10.1038/srep42563.
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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.
Published Version: doi:10.1038/srep42563
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335661/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071894
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