Picrosides-rich fraction from Picrorhiza kurroa attenuates steatohepatitis in zebrafish and mice by modulating lipid metabolism and inflammation.

BACKGROUND

Non-alcoholic steatohepatitis (NASH) has become a serious public health concern with high global prevalence. The lack of safe and efficient treatment for the condition demands exploring new therapeutic solutions.

PURPOSE: In the present study, we investigated the protective efficacy of picrosides-rich fraction (PF) from Picrorhiza kurroa against steatohepatitis and revealed the molecular mechanism of action.

METHODS

PF was prepared and characterized using UPLC analysis. Initially, the efficacy of PF was studied on the zebrafish model of NASH. Further, a Methionine and Choline-Deficient (MCD) diet-induced NASH model in mice was employed to evaluate the hepatoprotective efficacy of PF by utilizing biochemical, histopathological and molecular studies.

RESULTS

The UPLC analysis revealed the presence of 29.11% and 29.86% picroside I and II in the PF, respectively. In the zebrafish model of NASH, PF treatment reduced the hepatic lipid accumulation and modulated the expressions of lipogenic, inflammatory, oxidative, and cellular stress genes. Further, in MCD diet-induced NASH in mice, PF treatment showed a significant improvement in body weights and serum liver injury markers. Reduced degenerative changes and fibrous tissue was observed in the PF-treated groups. The downregulated expression of Srebp1c, Cd36, Fas, Chrebp, Pparγ, and Hnf4α showed anti-lipogenic potential of PF treatment. NASH development followed oxidative stress, mitochondrial dysfunction, and inflammation in the liver of mice. However, PF treatment encouraged mitochondrial biogenesis by upregulating Pgc1α, Tfam, and Nrf2 expressions. The elevated levels of NFκB, TNFα, IL6, TGFβ, and αSMA were also restored by PF, advocating its anti-inflammatory and anti-fibrogenic effect.

CONCLUSION

The present study revealed that PF ameliorate the progression of NASH by increasing mitochondrial biogenesis and decreasing lipogenesis, hepatic inflammation, and fibrosis.