CYP7A1 represents the key enzyme catalyzing BA biosynthesis. In one human study, investigating patients with obstructive cholestasis, hepatic CYP7A1 mRNA tended to be increased, similar to the results in our fatty liver patients.32 High serum cholestenone levels confirm the increased CYP7A1 mRNA expression in our study at the functional level. SHP also represses hepatocyte BA uptake by transcriptional repression of NTCP.33 In experimental obstructive cholestasis in rodents, NTCP is down-regulated by activation of FXR and subsequently induction of the repressor SHP. This mechanism prevents excessive BA transport from portal blood and uptake GDC-0980 into the hepatocytes.10

Similar mechanisms are in action for human NTCP where SHP has been shown to suppress the glucocorticoid receptor-mediated transactivation of the human NTCP promoter.34 In human fatty livers, we observed an increase in NTCP expression, which in contrast to Cyp7A1 decreased with progression to NASH. The observed attenuation of baseline SHP activity under steatotic conditions was confirmed in our in vitro experiments. FFA treatment led selleck chemicals llc to a significant up-regulation

of NTCP and Cyp7A1. Similar to our findings in NASH regarding NTCP expression, BA (CDCA) treatment attenuated these effects, most likely by way of FXR-SHP activation. This is consistent with recent data from ob/ob mice where SHP-induction and down-regulation of NTCP is absent despite retention of BAs.35 In a recent study, Wanninger et al.36 observed an up-regulation of hepatic CYP7A1 mRNA expression, in line with elevated serum triglyceride levels in adiponectin knockout

mice. We also observed lower adiponectin levels with advanced stages Ketotifen of NAFLD and our in vitro data also confirm a negative regulation of Cyp7A1 by adiponectin. As Aranha et al.6 have shown, BAs within the liver are elevated in patients with steatohepatitis. In agreement with our data, this would suggest an increased BA uptake and production. Elevated intrahepatic BA amounts would lead to activation of FXR and subsequently enhanced BSEP expression, which we also observed.29 On the other hand, impaired adaptation of BSEP expression may lead to increased BA accumulation in hepatocytes and enhanced cell death. Interestingly, steatotic hepatocytes were shown to be more susceptible to BA-induced apoptosis.37 Even low elevations of BAs normally not considered harmful could enhance hepatocyte apoptosis in patients with NAFLD. However, in our in vitro studies we did not observe alterations in viability upon FFA and CDCA cotreatment. An altered intestinal FGF19 production and/or altered hepatic responsiveness to FGF19 may accordingly contribute to the dysregulation of BA homeostasis observed in our patients with NAFLD, as has previously been shown that a rather moderate increase in BA flux may superimpose an influence of FGF15.