Potentially regulating the ApoB RNA editosome via FXR activation: The natural compound continentalic acid alleviates hepatic fibrogenesis.

BACKGROUND

Hepatic fibrosis is a reversible wound-healing response to acute or chronic liver injury, and currently lacks effective therapeutic drugs. Continentalic acid (CNT) is the effective ingredient from Aralia continentalis Kitag., used as medicinal and edible homologous plant, and exhibits anti-inflammatory and hepatoprotective effects.

PURPOSE: The study investigates the therapeutic effect of CNT against liver fibrosis and elucidates its potential molecular mechanism.

METHODS

HSCs or LX-2 cells were stimulated with TGF-β or conditioned medium from LPS-primed macrophages, and then cultured with CNT, GW4064 or Guggulsterone, or deficient FXR by siRNA. Hepatic fibrosis was induced in mice by TAA and subjected to treatment with CNT, Pirfenidone (PFD). Network pharmacology and molecular docking were used to predict potential targets of CNT. Finally, the necessity of FXR on CNT against hepatic fibrosis was validated in TAA induced model through FXR knockdown mediated by adeno-associated virus (AAV).

RESULTS

CNT significantly inhibited the accumulation of extracellular matrix (ECM) and inflammatory factors in activated HSCs. CNT effectively reduced liver collagen deposition and inflammatory response in TAA-induced mice. Network pharmacology and experimental verification showed that CNT could activate FXR to further inhibit Apobec1/A1CF. Validated by agonist, inhibitors, or FXR siRNA, the inhibition or knockdown of FXR significantly weakened the inhibitory effects of CNT on Apobec1/A1CF and HSCs activation. Chromatin immunoprecipitation (ChIP) assay further indicated that FXR can bind to the promoter region of the APOBEC1, implying a potential transcriptional regulatory function. CNT could regulate the crosstalk of macrophages and HSCs by activating FXR and inhibiting Apobec1/A1CF. FXR deficiency also blocked the regulation of CNT on activated HSCs stimulated with conditioned medium from macrophage. FXR knockdown significantly exacerbated TAA induced liver fibrosis formation and weakened the ability of CNT alleviating liver fibrosis in AAV-NR1H4 mice.

CONCLUSION

CNT could ameliorate hepatic fibrosis and HSCs activation, which might be potentially implicated in the activating FXR to inhibit ApoB production mediated by Apobec1/A1CF.