Abstract
AimBile 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.MethodsCell 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.ResultsEmodin 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.ConclusionEmodin has a protective effect and a rescue activity on cholestasis via stimulating FXR/BSEP pathways in promoting the canalicular export of accumulated bile.
Highlights
Intrahepatic cholestasis is characterized by disorders of bile formation, bile acid (BA) detoxification and its transport obstacles that are caused by the impairment of hepatocytes and cholangiocytes (Ding et al, 2008)
Compared with the control group, the mRNA expressions of Bile salt export pump (BSEP) and farnesoid X receptor (FXR) were significantly decreased in the guggulsterones group (p < 0.01), while compared with the guggulsterones group, the mRNA expressions of BSEP and FXR were significantly elevated in the emodin groups (p < 0.05 or 0.01) (Figures 2A,B)
The protein expressions of BSEP, FXR1, and FXR2, were significantly lowered by guggulsterones (p < 0.01), and compared with the guggulsterones group, the protein expressions of BSEP, uridine diphosphate glucuronosyltransferase 2 family polypeptide B4 (UGT2B4), FXR1, and FXR2 were significantly elevated in the emodin groups (p < 0.05 or 0.01) (Figures 2C–F)
Summary
Intrahepatic cholestasis is characterized by disorders of bile formation, bile acid (BA) detoxification and its transport obstacles that are caused by the impairment of hepatocytes and cholangiocytes (Ding et al, 2008). The amount of cholestasis treatment drugs is limited, due to a lack of evidence for evidence-based medicine and clinical curative effect. Ursodeoxycholic acid (UDCA) and S-adenosylmethionine are supported by more and more evidence, and the clinical studies have confirmed that the two kinds of drugs in the treatment of cholestatic liver disease, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy, are effective, the drugs are expensive and work slowly (Mato and Lu, 2007; Corpechot et al, 2008). It is urgent to develop new drugs with quick action and fewer side effects to treat cholestatic hepatitis
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