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 apigenins 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 apigenins anti-fibrotic activity.

... anti-fibrotic activity; indeed, apigenin dose-dependently reduced collagen I in the human HSC line, TWNT-4. To identify proteins mediating apigenins 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 apigenins anti-fibrotic activity. The hepatic stellate

...). Membrane blotting was performed using the following primary antibodies, rabbit polyclonal anti-COL1A1 antibody (Rockland, Limerick, PA, catalog #600-401-103) (1:5000), rabbit polyclonal anti-C1QTNF2 antibody (ProSci, catalog #3561) (1:1000), mouse monoclonal anti-GAPDH antibody (Millipore, catalog #CB1001) (1:2500), mouse monoclonal anti--tubulin (Sigma-Aldrich, catalog #T4026) (1:2500), mouse anti-calnexin (Abcam, catalog #75801) (1:2500) and appropriate HRP-conjugated secondary antibody. Bands were

... in the rabbit polyclonal anti-C1QTNF2 antibody (1:1000) with negative and positive controls, chicken polyclonal anti-GFAP (Abcam, catalog #4674) (1:200), and anti-Desmin (AbCam, catalog #15200) (1:200). Appropriate green fluorescent tagged secondary antibodies (Life Technologies) were used and DAPI was used for nuclear staining. Cells were imaged under Eclipse TS100 fluorescent microscope (Nikon). Culture activated mouse HSCs DNA microarray-based transcriptome profiles of mouse primary HSCs before (day 0) and after in vitro culture activation (day 7) were obtained from GEO database (NCBI Gene Expression Omnibus [GEO] accession number, GSE34949) 12 13 . Clinical HCV cirrhosis cohort DNA microarray-based transcriptome profiles of 216 patients with HCV-related compensated cirrhosis we previously reported were used to evaluate prognostic association of C1QTNF2 expression level (GSE15654) 6 . C1QTNF2 -high.group was defined as samples with C1QTNF2 expression higher than one standard

... protein level ( Fig. 1C ). Expression of PDGFRB , encoding platelet-derived growth factor receptor-, was similarly reduced by 10M of apigenin ( Fig. 1D ). Cell viability assessment showed that the compound is not toxic at concentrations below 20M ( Fig. 1E ). Other known liver fibrosis-related genes, ASMA, TGFB1 , and TGFBR1 , were not suppressed at the non-toxic concentration ( Fig. 1F H), suggesting that apigenins effect is directed to a specific subset of fibrogenesis-related pathways. C1QTNF2 as a

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Gene: C1QTNF2 - C1q and tumor necrosis factor related protein 2 - (NCBI)

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