title: Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory and Department of Intensive Care Medicine, University Hospitals KU Leuven, Belgium.
authors.forename: Yoo-Mee
authors.initials: YM
authors.lastname: Vanwijngaerden
authors.forename: Joost
authors.initials: J
authors.lastname: Wauters
authors.forename: Lies
authors.initials: L
authors.lastname: Langouche
authors.forename: Sarah
authors.initials: S
authors.lastname: Vander Perre
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Sally
authors.initials: S
authors.lastname: Coulter
authors.forename: Sara
authors.initials: S
authors.lastname: Vanderborght
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Alexander
authors.initials: A
authors.lastname: Wilmer
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
authors.forename: Dieter
authors.initials: D
authors.lastname: Mesotten
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000368:Aged; D001647:Bile Acids and Salts / Q000097:blood*; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000090702:Constitutive Androstane Receptor; D016638:Critical Illness; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D000090702:Constitutive Androstane Receptor; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D027981:Symporters; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C490280:SLC22A7 protein, human; C071908:sodium-bile acid cotransporter; C114462:multidrug resistance-associated protein 3