Data from hepatocyte-RXRα-null mice indicate that these mice are protected against WY-14,643-induced liver injury by the up-regulation of Mrp3 expression and increased efflux of BAs into blood for renal excretion.25 FXR knockout mice have a lower mortality rate and less liver injury during bile duct ligation. These FXR knockout mice strongly increased Mrp4 and reduced Bsep expression.26 However, FXR

knockout mice exhibit more hepatotoxicity when challenged with a CA-enriched diet.27 Also, FXR agonists could be beneficial learn more for patients with cholestatic liver diseases.28 CAR knockout mice show lower levels of serum and liver primary BAs than wildtype mice during bile duct ligation.29 Moreover, these CAR knockout mice are resistant to acetaminophen

liver toxicity.30 Similarly, an increased bilirubin clearance has been demonstrated in PXR knockout mice.31 Histopathology of ICU patient liver biopsies revealed classic changes of cholestasis, namely, bilirubinostasis, ductular proliferation, and variable inflammation. Increased levels of serum bilirubin and conjugated BAs correlated strongly with the microscopic signs of bilirubinostasis and ductular reaction. Ductular proliferation and ductular differentiation of the hepatocytes are considered part of an adaptive, protective response to cholestasis. Canalicular MDR3 was also up-regulated in ICU patients. Given the key role of biliary phospholipids in protecting bile duct epithelium from the potentially toxic biliary content, up-regulation of MDR3 might also exert a compensatory action, protecting the canalicular membrane and biliary epithelium. Because this website MRP3 correlated well with histological bilirubinostasis and serum bilirubin and conjugated BAs levels, MRP3 up-regulation is a likely compensatory reaction to cholestasis, as has been observed in animal bile duct ligation models

of cholestasis.32 The up-regulation of MRP3 (and MRP4) provides a mechanism to limit hepatocellular retention of hydrophobic BAs and other potentially toxic compounds that would normally be destined for biliary excretion. This is in Tangeritin keeping with the selective increase in serum taurine and glycine conjugated BAs, which have been conjugated by hepatocytes and transported back into the circulation. MRP3 up-regulation has also been shown in acute sepsis models without longer-lasting cholestasis.33 Unexpectedly, there was a lack of association between ICU cholestasis and markers of inflammation, suggesting that inflammation is not the main contributor to cholestasis in prolonged critical ill patients, as it does in acute sepsis or septic shock.8 A limitation of this study is reliance on liver biopsy samples taken immediately postmortem, which is an inherent confounder. However, ethically it was not possible to obtain study-programmed liver samples in unselected critically ill patients.