Abstract
Intrahepatic cholestasis, a clinical syndrome, is caused by excessive accumulation of bile acids in body and liver. Proper regulation of bile acids in liver cells is critical for liver injury. We previously reported the effects of dioscin against α-naphthylisothio- cyanate (ANIT)-induced cholestasis in rats. However, the pharmacological and mechanism data are limited. In our work, the animals of rats and mice, and Sandwich-cultured hepatocytes (SCHs) were caused by ANIT, and dioscin was used for the treatment. The results showed that dioscin markedly altered relative liver weights, restored ALT, AST, ALP, TBIL, GSH, GSH-Px, MDA, SOD levels, and rehabilitated ROS level and cell apoptosis. In mechanism study, dioscin not only significantly regulated the protein levels of Ntcp, OAT1, OCT1, Bsep and Mrp2 to accelerate bile acids excretion, but also regulated the expression levels of Bak, Bcl-xl, Bcl-2, Bax, Caspase 3 and Caspase 9 in vivo and in vitro to improve apoptosis. In addition, dioscin markedly inhibited PI3K/Akt pathway and up-regulated the levels of Nrf2, GCLc, GCLm, NQO1 and HO-1 against oxidative stress (OS) caused by bile acids. These results were further validated by inhibition of PI3K and Akt using the inhibitors of wortmannin and perifosine in SCHs. Our data showed that dioscin had good action against ANIT-caused intrahepatic cholestasis through regulating transporters, apoptosis and OS. This natural product can be considered as one active compound to treat intrahepatic cholestasis in the future.
Highlights
Intrahepatic cholestasis is one common and acquired liver disease (Fuentes-Broto et al, 2009; Anwer, 2014)
Bilirubin is produced by the hepatic organic anion transporting polypeptides (OATPs) and organic cation transporters (OCTs), which is secreted into the tubules through multidrug resistance associated protein 2 (Mrp2) (Zollner et al, 2001; Kalliokoski and Niemi, 2009; Saeki et al, 2011)
We found that dioscin had good effects against liver fibrosis (Liu et al, 2015; Zhang et al, 2015), acute liver damages (Lu et al, 2012; Yao et al, 2016), obesity (Liu et al, 2015), osteoporosis (Tao et al, 2016), renal and hepatic ischemia/reperfusion injury (Tao et al, 2014; Qi et al, 2015)
Summary
Intrahepatic cholestasis is one common and acquired liver disease (Fuentes-Broto et al, 2009; Anwer, 2014). Current studies have focused on bile acid transporter dysregulation, oxidative stress (OS), hepatocyte apoptosis and inflammation associated with cholestasis (Roma and Sanchez Pozzi, 2008; Gonzalez-Sanchez et al, 2015). Cholestasis is defined as the impairment of bile and bilirubin. Dioscin Protects ANIT-Induced Intrahepatic Cholestasis secretion (Schmitt et al, 2000), and which the accumulation of bile salts can affect the functions and expression levels of some transporters in hepatocytes (Akita et al, 2001; Kawai et al, 2007). Bile acid and bilirubin can be excreted from liver via Na+-taurocholate co-transporting polypeptide (Ntcp) and Bsep (Meier and Stieger, 2002; Arrese and Trauner, 2003). Regulating the expression levels and functions of these membrane transporters might improve cholestasis
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