Eriocitrin ameliorates hepatic fibrosis and inflammation: The involvement of PPARα-mediated NLRP1/NLRC4 inflammasome signaling cascades.

Abstract

Ethnopharmacological relevance: Citri Reticulatae Pericarpium (Chenpi) is a traditional Chinese medicine and recorded to have hepatoprotective therapeutic and condition value. Eriocitrin (ER) a natural compound isolated from Citri Reticulatae Pericarpium may ameliorate hepatic inflammation in chronic liver diseases.

Aim of the study: The current study investigates the hepatoprotective effect and potential mechanism of ER against hepatic fibrosis.

Materials and methods: The hepatic fibrosis mouse model was constructed by intraperitoneally injecting thioacetamide (TAA) for five weeks. Hepatic stellate cells (HSCs) were treated with transforming growth factor-β (TGF-β). Meanwhile, lipopolysaccharide/adenosine triphosphate (LPS/ATP) was given to excite the normal mouse bone marrow-derived macrophages (BMDMs), and thus the cells could acquire the conditioned medium. Moreover, LX-2 cells were administrated with PPARα knockdown vector (siRNA-PPARα).

Results: RNA sequencing studies revealed that in mice induced by TAA, the PPARα/NOD-like receptor/ neutrophil extracellular traps (NETs) significantly influence ER-based hepatic protection. In TAA-induced mice, ER could up-regulate PPARα and down-regulate NLRP1/NLRC4 and the development of NETs. Our findings indicated that ER significantly up-regulated PPARα, inhibited NLRP1/NLRC4 inflammasome in HSCs. Deficiency of PPARα in the activated LX-2 weakened the regulatory effect of ER on inhibiting the NLRP1/NLRC4 inflammasome. In addition, ER might hinder the activation of BMDMs and also obstruct IL-1β and IL-6 passage in the extracellular space.

Conclusions: The results indicated that ER decreased inflammation by controlling the PPARα-NLRP1/NLRC4 signaling pathway and inhibiting fibril formation. Collectively, our results underscore the therapeutic potential of ER in addressing hepatic fibrosis.