Abstract
Adelmidrol, an anti-inflammatory small-molecule compound, can treat inflammatory diseases like arthritis and colitis in a PPARγ-dependent manner. Effective anti-inflammatory therapy is beneficial in delaying the progression of liver fibrosis. This study aimed to investigate the effect and underlying mechanisms of adelmidrol on hepatic fibrosis induced by CCl4 and CDAA-HFD. In the CCl4 model, adelmidrol (10 mg/kg) significantly reduced the incidence of liver cirrhosis from 76.5% to 38.9%, with a reduction of ALT, AST, and extracellular matrix deposition. RNA-seq revealed adelmidrol markedly inhibited the activation of hepatic scar-associated Trem2+ macrophages and PDGFRα+ stellate cells. Adelmidrol exhibited a limited anti-fibrotic effect in CDAA-HFD-induced fibrosis. Further, inconsistencies were observed in the expression trends in liver PPARγ in both models. CCl4 injury led to the continuous decrease in hepatic PPARγ levels, adelmidrol treatment up-regulated hepatic PPARγ expression and down-regulated the expression of pro-inflammatory factor NF-κB and pro-fibrotic factor TGF-β1. Adelmidrol also inhibited the activation of macrophages and HSCs in a PPARγ-dependent manner in vitro. GW9662, a specific PPARγ antagonist, counteracted the anti-fibrotic effect of adelmidrol. In CDAA-HFD-induced model, hepatic PPARγ expression gradually increased with the progress of modeling. Adelmidrol enhanced steatosis in hepatocytes by the activation of the PPARγ/CD36 pathway in the CDAA-HFD model and FFA-treated HepG2, showing a limited anti-fibrotic effect. GW9662 reversed the pro-steatotic effect of adelmidrol and improved fibrosis. The anti-fibrotic outcomes of adelmidrol were related to hepatic PPARγ levels, which depends on the synergistic effect of PPARγ agonism caused by adelmidrol on hepatocytes, macrophages, and HSCs in different pathological states.