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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article number42563
JournalScientific reports
Volume7
DOIs
StatePublished - Mar 3 2017
Externally publishedYes

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Apigenin
Hepatic Stellate Cells
Transcriptome
Fibrosis
Liver
Collagen
Complement C1q
Proteins
Adipokines
Drug Discovery
Hepatitis C
Flavonoids
Tumor Necrosis Factor-alpha
Databases
Gene Expression
Cell Line
Wounds and Injuries
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • General

Cite this

Hicks, D. F., Goossens, N., Blas-García, A., Tsuchida, T., Wooden, B., Wallace, M. C., ... Friedman, S. L. (2017). Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells. Scientific reports, 7, [42563]. https://doi.org/10.1038/srep42563

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

In: Scientific reports, Vol. 7, 42563, 03.03.2017.

Research output: Contribution to journalArticle

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 & Friedman, SL 2017, 'Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells', Scientific reports, vol. 7, 42563. https://doi.org/10.1038/srep42563
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. / Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells. In: Scientific reports. 2017 ; Vol. 7.
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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.",
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