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Digestive Diseases and Sciences

, Volume 60, Issue 11, pp 3318–3328 | Cite as

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

  • Brian C. Ferslew
  • Guoxiang Xie
  • Curtis K. Johnston
  • Mingming Su
  • Paul W. Stewart
  • Wei Jia
  • Kim L. R. Brouwer
  • A. Sidney BarrittIVEmail author
Original Article

Abstract

Background and Aims

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.

Keywords

Nonalcoholic steatohepatitis Bile acids Bile acid metabolome Enterohepatic recirculation 

Abbreviations

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

CA

Cholate

CDCA

Chenodeoxycholate

DCA

Deoxycholate

LCA

Lithocholate

HCA

Hyocholate

MCA

Muricholate

HDCA

Hyodeoxycholate

FXR

Farnesoid X receptor

PXR

Pregnane X receptor

NAS

Nonalcoholic fatty liver disease activity score

AUC

Area under the curve

OPLS-DA

Orthogonal partial least squares-discriminant analysis

HOMA-IR

Homeostatic model for assessing insulin resistance

BAAT

Bile acid coenzyme A:amino acid N-acyltransferase

Notes

Acknowledgments

The authors would like to sincerely thank Drs. Nathan D. Pfeifer, Mary F. Paine, and Dhiren R. Thakker for insightful discussions throughout the development, conduct, and analysis of this study. The authors also would like to thank Kevin B. Harris and Dr. Eleftheria Tsakalozou for assistance with study conduct and data management, and Lisa Hardee for assistance performing FibroScan® measurements. Phoenix WinNonlin software was generously provided to the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, by Certara as a member of the Pharsight Academic Center of Excellence Program. This project was supported in part by the National Institutes of Health, National Center for Advancing Translational Sciences (NCATS), through Award Number 1UL1TR001111, National Institute of General Medical Sciences through Award Number R01 GM041935 [K. L. R. B], an Amgen Predoctoral Fellowship in Pharmacokinetics and Drug Disposition [B. C. F.], and Quintiles Pharmacokinetics/Pharmacodynamics Fellowships [C. K. J.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, Amgen or Quintiles.

Conflict of interest

The authors have no conflict of interest to disclose.

Supplementary material

10620_2015_3776_MOESM1_ESM.docx (42 kb)
Supplementary material 1 (DOCX 43 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Brian C. Ferslew
    • 1
    • 2
  • Guoxiang Xie
    • 3
  • Curtis K. Johnston
    • 1
  • Mingming Su
    • 3
  • Paul W. Stewart
    • 4
  • Wei Jia
    • 3
  • Kim L. R. Brouwer
    • 1
  • A. Sidney BarrittIV
    • 5
    Email author
  1. 1.Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Clinical Pharmacology and Drug Metabolism and PharmacokineticsTheravance Biopharma US, Inc.South San FranciscoUSA
  3. 3.Metabolomics Shared ResourceUniversity of Hawaii Cancer CenterHonoluluUSA
  4. 4.Department of Biostatistics, UNC Gillings School of Global Public HealthUniversity of North Carolina at Chapel HillChapel HillUSA
  5. 5.Division of Gastroenterology and Hepatology, UNC School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA

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