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 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.

Weighted correlation network bioinformatics uncovers a key molecular biosignature driving the left-sided heart failure

“…A study revealed that SMOC2 could modulate fibroblast proliferation and extracellular matrix deposition [43]. Similarly, a study revealed that expression of C1QTNF2 related to anti-fibrotic function [44]. Thus, SMOC2 and C1QTNF2 might play a similar function to protect from cardiac fibrosis.…”

Mechanisms and disease consequences of nonalcoholic fatty liver disease

“…In addition, several circulating molecules derived from other tissues can promote fibrotic responses in the liver through direct or indirect actions on hepatic stellate cells (see below). Informaticsbased approaches are increasingly utilized to uncover molecular signatures from tissue and stellate cells that can identify targets and predict outcomes (Hicks et al, 2017;Marcher et al, 2019;Ramnath et al, 2018;Wooden et al, 2017). From such studies, transcriptional (Marcher et al, 2019) and epigenetic (Moran- Sal-vador et al, 2019) drivers can be inferred and are remarkably conserved across different models of cellular activation, suggesting that stellate cell activation is a common pathway downstream of multiple fibrogenic signals in liver injury.…”

The Potential and Action Mechanism of Polyphenols in the Treatment of Liver Diseases

“…Upon chronic liver injury, quiescent HSCs undergo morphological and phenotypical transdifferentiation into contractile and highly proliferative myofibroblasts with collagen-producing ability. Plenty of polyphenols were found to protect liver from fibrosis via suppression of the activation of HSCs such as apigenin, EGCG, quercetin, icaritin, curcumin, and resveratrol [ 107 – 113 ]. The mechanisms underlying the inhibition of activated HSCs have been ascribed to upregulation of C1QTNF2, MMPs, or miR-221 to accelerate osteopontin degradation and downregulation of PPAR γ or membrane translocation and gene expression of GLUT2.…”