Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression

Hyperbilirubinemia is common during critical illness and is associated with adverse outcome. Whether hyperbilirubinemia reflects intensive care unit (ICU) cholestasis is unclear. Therefore, the aim of this study was to analyze hyperbilirubinemia in conjunction with serum bile acids (BAs) and the key steps in BA synthesis, transport, and regulation by nuclear receptors (NRs). Serum BA and bilirubin levels were determined in 130 ICU and 20 control patients. In liver biopsies messenger RNA (mRNA) expression of BA synthesis enzymes, BA transporters, and NRs was assessed. In a subset (40 ICU / 10 controls) immunohistochemical staining of the transporters and receptors together with a histological evaluation of cholestasis was performed. BA levels were much more elevated than bilirubin in ICU patients. Conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA) were elevated, with an increased CA/CDCA ratio. Unconjugated BA did not differ between controls and patients. Despite elevated serum BA levels, CYP7A1 protein, the rate‐limiting enzyme in BA synthesis, was not lowered in ICU patients. Also, protein expression of the apical bile salt export pump (BSEP) was decreased, whereas multidrug resistance‐associated protein (MRP) 3 was strongly increased at the basolateral side. 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;)

[1]  K. Lindor.  Farnesoid X receptor agonists for primary biliary cirrhosis , 2011, Current opinion in gastroenterology.

[2]  R. Evans,et al.  Extrahepatic Cancer Suppresses Nuclear Receptor–Regulated Drug Metabolism , 2011, Clinical Cancer Research.

[3]  A. Peterson,et al.  FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways , 2011, PloS one.

[4]  M. Trauner,et al.  Nuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity. , 2010, Pharmacology & therapeutics.

[5]  J. Chiang,et al.  Bile acids: regulation of synthesis , 2009, Journal of Lipid Research.

[6]  Wen Xie,et al.  PXR and CAR in energy metabolism , 2009, Trends in Endocrinology & Metabolism.

[7]  G. Van den Berghe,et al.  The effect of strict blood glucose control on biliary sludge and cholestasis in critically ill patients. , 2009, The Journal of clinical endocrinology and metabolism.

[8]  Y. Wan,et al.  69 MECHANISMS OF RESISTANCE OF HEPATOCYTE RETINOID X RECEPTOR ALPHA-NULL MICE TO WY-14,643-INDUCED HEPATOCYTE PROLIFERATION AND CHOLESTASIS , 2009 .

[9]  Johan Auwerx,et al.  Targeting bile-acid signalling for metabolic diseases , 2008, Nature Reviews Drug Discovery.

[10]  G. Van den Berghe,et al.  Effect of insulin therapy on coagulation and fibrinolysis in medical intensive care patients* , 2008, Critical care medicine.

[11]  P. Metnitz,et al.  Incidence and prognosis of early hepatic dysfunction in critically ill patients—A prospective multicenter study , 2007, Critical care medicine.

[12]  V. Bansal,et al.  Jaundice in the intensive care unit. , 2006, The Surgical clinics of North America.

[13]  M. Trauner,et al.  Mechanisms of Disease: mechanisms and clinical implications of cholestasis in sepsis , 2006, Nature Clinical Practice Gastroenterology &Hepatology.

[14]  M. Trauner,et al.  Molecular mechanisms of cholestasis , 2006, Wiener Medizinische Wochenschrift.

[15]  G. Van den Berghe,et al.  Intensive insulin therapy in the medical ICU. , 2006, The New England journal of medicine.

[16]  T. Fiore,et al.  Jaundice in critical illness: promoting factors of a concealed reality , 2006, Intensive Care Medicine.

[17]  Ilse Vanhorebeek,et al.  Intensive insulin therapy protects the endothelium of critically ill patients. , 2005, The Journal of clinical investigation.

[18]  S. Poloyac,et al.  Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice , 2005, Hepatology.

[19]  R. Evans,et al.  Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Karpen,et al.  Endotoxin leads to rapid subcellular re-localization of hepatic RXRα: A novel mechanism for reduced hepatic gene expression in inflammation , 2004, Nuclear receptor.

[21]  Ning Li,et al.  Lipopolysaccharide-mediated regulation of hepatic transporter mRNA levels in rats. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[22]  C. Liddle,et al.  Feed-forward Regulation of Bile Acid Detoxification by CYP3A4 , 2004, Journal of Biological Chemistry.

[23]  K. Zatloukal,et al.  Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. , 2003, Gastroenterology.

[24]  D. Moore,et al.  Modulation of Acetaminophen-Induced Hepatotoxicity by the Xenobiotic Receptor CAR , 2002, Science.

[25]  J. Boyer,et al.  Cellular localization and up‐regulation of multidrug resistance–associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver , 2001, Hepatology.

[26]  Masahiro Tohkin,et al.  Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis , 2000, Cell.

[27]  G. Hooiveld,et al.  Upregulation of the multidrug resistance genes mrp1 and mdr1b and downregulation of the organic anion transporter mrp2 and bile salt transporter spgp in endotoxemic rat liver , 1998 .

[28]  P. Meier,et al.  The Sister of P-glycoprotein Represents the Canalicular Bile Salt Export Pump of Mammalian Liver* , 1998, The Journal of Biological Chemistry.

[29]  D. Keppler,et al.  The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. , 1997, Gastroenterology.

[30]  H. O. Wheeler,et al.  The relationship between taurocholate secretion rate and bile production in the unanesthetized dog during cholinergic blockade and during secretin administration. , 1962, The Journal of clinical investigation.

[31]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. , 2009, Chest.

[32]  A. Burns,et al.  Nuclear export of retinoid X receptor alpha in response to interleukin-1beta-mediated cell signaling: roles for JNK and SER260. , 2006, The Journal of biological chemistry.

[33]  B. Bistrian,et al.  Intensive insulin therapy in critically ill patients. , 2002, The New England journal of medicine.