The present data suggest that

The present data suggest that the decrease of liver BAs was mainly due to the decrease of hepatic BAs synthesis because the BA synthetic enzymes Cyp7a1, Cyp7b1 and Cyp8b1 were markedly reduced. The increase may also be due to the increase of hepatic BAs efflux, because the liver BA efflux transporter Bsep was induced. As a major transporter for the secretion of bile acids from hepatocytes into bile, Bsep mainly mediates the excretion of conjugated BAs into bile (Hayashi et al., 2005). The present study demonstrated that 9HSW influenced bile acids homeostasis with decreasing in circulating total BAs and all major bile Cabazitaxel sub-types in liver compared with control group, mainly due to decrease of TCA and TMCA in liver. No significant changes were found in CA and DCA. Additionally, reduction of CA and MCA contributed to the lower serum BA content. The decrease was not due to increased active transport of BAs in the ileum, because HSW had a tendency to increase the uptake transporter Asbt, however, this increase was not statistically significant. The up-regulation of Ntcp could be a compensatory action for bile acid efflux Bsep-mediated BA excretion impairment, to remain the homeostasis of bile acids in hepatocyte. The current study demonstrated BA homeostasis were regulated via two feedback loop operated by Fxr-Shp in the liver and Fxr-Fgf15 in the intestine (Kong et al., 2012). The feedback suppression of Cyp7a1 gene transcription by FXR is one of the most important mechanisms in the maintenance of BA homeostasis (Degirolamo et al., 2014). We discovered HSW induced the expression of the direct FXR target gene Shp (1.55 times) in liver. In the ileum, the expression of the direct FXR target gene Shp (6.89 times) and Fgf15 (3.37 times) were increased. Collectively, HSW-mediated suppression of Cyp7a1 in the liver was mainly due to the activation of the Fxr-Fgf15 signaling in the intestines. Asbt is the major uptake transporter, together with Ostα/β and Mrp2 are three efflux transporters responsible for BA uptake and secretion in ileum, respectively (Dawson et al., 2009). The present study has demonstrated that although HSW had little effect on the concentration of total BAs in the ileum, HSW had the tendency to increase these four transporters without statistical significance, a shift was thereby caused by HSW in intestine bile acid metabolism. The change in the composition of bile acids were characterized by the increase of unconjugated bile acids (CA, MCA, CDCA, DCA) that are naturally occurring agonist of Fxr. Collectively, HSW induced the unconjugated bile acids secretion, as the agonist of Fxr, activate Fxr-Fgf15, further to inhibit the Cyp7a1 expression (Fig. 8). In conclusion, the present study comprehensively elucidated the role of HSW in BA composition, BA synthesis, transport and regulation, and it was found that short time treatment cannot cause liver injury, but decrease BA concentrations in hepatocytes. These changes were potentially linked to Cyp7a1 down regulation and BA excretion regulated by Bsep. The elevation of unconjugated BAs activates Fxr-Fgf15 signal pathway and further inhibited the BA synthetic enzyme in the liver. Based on the results, in the further study, it would be interesting to investigate the effective of HSW on BA homeostasis with a long time administration. Previous research has shown that synthesis, metabolism, clearance and intestinal absorption of BAs can be enrolled in liver disease. HSW-induced hepatotoxicity belongs to idiosyncratic drug-induced liver injury (Li et al., 2016). It is of great significance to explore whether HSW medication will aggravate liver damage of the patients with abnormal bile acid metabolism.
Acknowledgments This work was supported by the Important Drug Develop of MOST, China (2015ZX09501004-003-004), Special Scientific Research for Traditional Chinese Medicine of State Administration of Traditional Chinese Medicine of the People's Republic of China (201507004) and Tianjin Science and Technology Program: Tianjin TCM Clinical Medicine Research Center (No. 15ZXLCSY00020).