Emodin Rescues Intrahepatic Cholestasis via Stimulating FXR/BSEP Pathway in Promoting the Canalicular Export of Accumulated Bile

Abstract

Aim Bile salt export pump (BSEP) have been confirmed to play an important role for bile acid canalicular export in the treatment of cholestasis. In this study, we investigated the stimulatory effect of emodin on BSEP signaling pathway in cholestasis. Methods Cell and animal experiments were given different concentrations of emodin. The BSEP upstream molecule farnesoid X receptor was down-regulated by small interfering RNA (siRNA) technology or guggulsterones and up-regulated by lentivirus or GW4064. Real-time PCR and Western blotting was employed to detect the mRNA and protein levels of BSEP in LO2 cell, rat primary hepatocytes and liver tissue. Immunohistochemistry (IHC) was used to examine the expression of BSEP in liver tissues. Rat liver function and pathological changes of liver tissue were performed by biochemical test and hematoxylin and eosin (HE) staining. Results Emodin could increase the mRNA and protein expression of BSEP and FXR. When down-regulating farnesoid X receptor expression with the siRNA or inhibitor guggulsterones, and up-regulating farnesoid X receptor expression with the lentivirus or agonist GW4064, emodin could increase the mRNA level of BSEP and FXR and the protein level of BSEP, FXR1, and FXR2. Emodin also had a notable effect on rat primary hepatocytes experiment, rat pathological manifestation, BSEP, FXR1, and FXR2 positive staining in liver tissues and the test of liver function. Conclusion Emodin has a protective effect and a rescue activity on cholestasis via stimulating FXR/BSEP pathways in promoting the canalicular export of accumulated bile.

Li-Dan-He-Ji Improves Infantile Cholestasis Hepatopathy Through Inhibiting Calcium-Sensing Receptor-Mediated Hepatocyte Apoptosis

“…In vivo study, we used ANIT to establish the rat model of hepatotoxicity (Ding et al, 2016;Xiong et al, 2019) and evaluate the effects of LDHJ granules on intrahepatic cholestasis (Kossor et al, 1993). Consistent with the previously reported findings (Wang et al, 2014), the increased levels of biomarkers (TBA, TBIL, DBIL, AST, ALT, ALP, and g-GT) and abnormal histopathological changes were observed in the liver of young rats with ANIT-induced intrahepatic cholestasis.…”

“…The protective effects of forsythoside-A and chlorogenic acid on cell apoptosis have been reported (Ali et al, 2017;Yan et al, 2017). Our research group has found the rescue activity of emodin on the intrahepatic cholestasis (Ding et al, 2016;Xiong et al, 2019). So forsythoside-A, emodin, chlorogenic acid may be promising in representing the LDHJ for further cell experiments.…”

“…Nowadays the nuclear receptors such as farnesoid X receptor (FXR) or pregnane X receptor (PXR), have been recognized as potential therapeutic targets in cholestasis (Gonzalez-Sanchez et al, 2015;Beuers et al, 2015). Our group have carried out some studies on emodin alleviating intrahepatic cholestasis by regulation of liver FXR pathway (Ding et al, 2016;Xiong et al, 2018;Xiong et al, 2019). The exploration of LDHJ on FXR target and relevant transporters and synthesic enzymes of bile acid is in progress and the results will be reported later.…”

Natural products for the prevention and treatment of cholestasis: A review

“…In addition, emodin also exerted its beneficial effect on ANIT‐induced cholestasis through antioxidative and antiinflammatory activities. The mechanism correlated with stimulating FXR/BSEP pathways in promoting the canalicular export of accumulated bile (Xiong et al, ). However, a paradoxical result occurred with the effects on ANIT‐induced cholestasis and hepatotoxicity in mice.…”

Five Constituents in Psoralea corylifolia L. Attenuate Palmitic Acid-Induced Hepatocyte Injury via Inhibiting the Protein Kinase C-α/Nicotinamide-Adenine Dinucleotide Phosphate Oxidase Pathway

“…2014010). A two-step collagenase digestion method was used and cultivated following the steps published by our research group (Xiong et al, 2019). Extracted hepatocytes were cultured in Dulbecco's modified Eagle medium/F-12 medium supplemented with 10% fetal bovine serum, 100 units/ ml penicillin, and 100 mg/ml streptomycin in 5% CO 2 /95% air at 37°C.…”