Honokiol attenuates ductular reaction, regulates of bile acids metabolism, and inhibits inflammatory response in murine cholestatic liver injury model

Abstract

Chronic cholestasis liver injury occurs in progressive hepatobiliary diseases that eventually lead to end-stage liver problems without curable treatment. Great advances in the molecular mechanism suggest the therapeutic pathways for the regulation of bile acid (BA) metabolism and inflammation response. Honokiol (HNK) is a natural ingredient from herb Magnolia officinalis that is used for eliminating toxins, reducing stagnation, resolving stasis and enhancing body immunity. In the present study, we designed two dependent experiments for the evaluation of the hepatoprotective and hepatotoxicity effects of HNK. Chronic cholestasis liver injury model was established by 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet feed for 4 weeks that featured as a ductular reaction, BAs accumulation, fibrosis and inflammatory response. In the first experiment, two dosages of HNK (2 and 10 mg/kg) were daily intraperitoneal injected from day 15 to day 28 for the treatment of chronic cholestasis liver injury. HNK displayed a dosage-dependent reduction of ductular reaction, regulation of BAs metabolism, remission of fibrosis and inhibition of inflammatory response. In the second experiment, the high dosage of HNK (10 mg/kg) was daily intraperitoneal injected into normal control and model mice for 4 weeks. HNK-mediated hepatoprotective effect is mainly involved in the regulation of BAs metabolism, decrease of inflammatory cell infiltration and inhibition of pro-inflammatory cytokines production. Moreover, HNK showed no hepatotoxicity even though the high dosage of HNK treatment for 28 days in control mice resulted in no obvious change in hepatic histopathological and serological changes. In conclusion, HNK exerts dosage-dependent pharmacological effect against DDC diet-induced chronic cholestasis liver injury. Further investigation of the preclinical pharmacodynamics effect and toxicity research about HNK is helpful for active therapeutic drug development for the treatment ofcholestasis liver disease.