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Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

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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.

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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

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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.

Author information

Authors and Affiliations

  1. 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

    Brian C. Ferslew, Curtis K. Johnston & Kim L. R. Brouwer

  2. Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., 901 Gateway Blvd, South San Francisco, CA, 94080, USA

    Brian C. Ferslew

  3. Metabolomics Shared Resource, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA

    Guoxiang Xie, Mingming Su & Wei Jia

  4. 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 W. Stewart

  5. 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

    A. Sidney Barritt IV

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  1. Brian C. Ferslew
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Correspondence to A. Sidney Barritt IV.

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Ferslew, B.C., Xie, G., Johnston, C.K. et al. Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis. Dig Dis Sci 60, 3318–3328 (2015). https://doi.org/10.1007/s10620-015-3776-8

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