This reversal of BA transport toward the sinusoidal blood compartment is in line with the increased serum conjugated BA levels. Immunostaining

showed marked down-regulation of nuclear farnesoid X receptor, retinoid X receptor alpha, constitutive androstane receptor, and pregnane X receptor nuclear protein levels. Conclusion: Failure to inhibit BA synthesis, up-regulate canalicular BA export, and localize pivotal NR in the hepatocytic nuclei may indicate dysfunctional feedback regulation by increased BA levels. Alternatively, critical illness may result in maintained BA synthesis (CYP7A1), reversal of normal BA transport (BSEP/MRP3), and inhibition of the BA sensor (FXR/RXRα) to increase serum BA levels. (HEPATOLOGY 2011;) Almost 20% of the intensive Tamoxifen care unit (ICU) patients develop ICU jaundice or cholestasis, which has been linked to an increased risk of mortality and length of stay.1, 2 Currently there is no consensus on the definition of cholestasis during critical illness. Most commonly, routine laboratory measurements of bilirubin

and alkaline phosphatase (ALP)/gamma-glutamyl transpeptidase (GGT) with different cutoffs are used.2-4 Therefore, in clinical practice ICU cholestasis is the equivalent of conjugated hyperbilirubinemia. Because a causal link between hyperbilirubinemia and worse outcome is missing, it may even be a biochemical epiphenomenon. Additionally, the reliability of hyperbilirubinemia as a marker of cholestasis in critically ill patients may be questionable, because there are many factors that can influence the levels of bilirubin. The weakness of bilirubin as a marker of cholestasis selleck kinase inhibitor during critical illness and the absent mechanistic underpinning of ICU cholestasis

were the main drivers for this study. To date, the behavior and impact of bile acids (BAs) during ICU jaundice has been neglected, despite their crucial role in bile formation,5 lipid/cholesterol metabolism, and energy and glucose homeostasis.6 Also, studies of the BA transporters and their regulatory network of nuclear receptors (NRs) has so far been focused on either chronic cholestatic liver disorders, such as primary Verteporfin research buy biliary cirrhosis, or familial intrahepatic cholestasis,7 or on acute animal models of sepsis.8 Endotoxin-induced proinflammatory cytokines lead to reduced Na+/taurocholate cotransporting polypeptide (NTCP) and organic anion transporting polypeptide (OATP) expression.8 Expression of the canalicular efflux pumps, bile salt export pump (BSEP), and multidrug resistance-associated protein (MRP) 2 is reduced during rat endotoxemia, whereas multidrug resistance protein (MDR) 1 expression is increased.8 MRP3 and MRP4, inducible basolateral efflux pumps, are strongly up-regulated and may serve as an alternative escape route for cytotoxic compounds from hepatocytes into sinusoidal blood.7 BA metabolism and transporter function is regulated by a complex network of NRs, together with their coactivators and corepressors.