title: Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis.
abstract: OBJECTIVE
  The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal.
  
  
  METHODS
  Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine.
  
  
  RESULTS
  Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595-3549 µM and healthy 1171-1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444-5898 µM and healthy 2634-2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile.
  
  
  CONCLUSIONS
  Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Kerr Hall, CB #7569, Chapel Hill, NC, 27599, USA. bferslew@theravance.com.|Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., 901 Gateway Blvd, South San Francisco, CA, 94080, USA. bferslew@theravance.com.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Ferslew
authors.affiliation: Metabolomics Shared Resource, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. GXie@cc.hawaii.edu.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Xie
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Kerr Hall, CB #7569, Chapel Hill, NC, 27599, USA. curtis.k.johnston@gmail.com.
authors.forename: Curtis K
authors.initials: CK
authors.lastname: Johnston
authors.affiliation: Metabolomics Shared Resource, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. MSu@cc.hawaii.edu.
authors.forename: Mingming
authors.initials: M
authors.lastname: Su
authors.affiliation: Department of Biostatistics, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 3105G McGavran-Greenberg Hall, Chapel Hill, NC, 27599, USA. Paul_Stewart@unc.edu.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Stewart
authors.affiliation: Metabolomics Shared Resource, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. WJia@cc.hawaii.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Kerr Hall, CB #7569, Chapel Hill, NC, 27599, USA. kbrouwer@unc.edu.
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.affiliation: Division of Gastroenterology and Hepatology, UNC School of Medicine, University of North Carolina at Chapel Hill, 8004 Burnett Womack, CB #7584, Chapel Hill, NC, 27599-7584, USA. sid_barritt@med.unc.edu.
authors.forename: A Sidney
authors.initials: AS
authors.lastname: Barritt
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D016002:Discriminant Analysis; D005215:Fasting / Q000097:blood; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000175:diagnosis; D019518:Postprandial Period; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers
keywords: Bile acid metabolome; Bile acids; Enterohepatic recirculation; Nonalcoholic steatohepatitis