Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis
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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.
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.
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.
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.
KeywordsNonalcoholic steatohepatitis Bile acids Bile acid metabolome Enterohepatic recirculation
Nonalcoholic fatty liver disease
Farnesoid X receptor
Pregnane X receptor
Nonalcoholic fatty liver disease activity score
Area under the curve
Orthogonal partial least squares-discriminant analysis
Homeostatic model for assessing insulin resistance
Bile acid coenzyme A:amino acid N-acyltransferase
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.
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