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Author Notes:

Address correspondence to: Paul A. Dawson, PhD, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Health Sciences Research Building, 1760 Haygood Drive, Suite E200, Office E206, Atlanta, Georgia 30322. e-mail: paul.dawson@emory.edu; fax: (404) 727-5737

Author contributions: Courtney Ferrebee, Paul Dawson, Brian Robinson, and Rheinallt Jones were responsible for the study concept and design; Courtney Ferrebee, Jianing Li, Jamie Haywood, Kimberly Pachura, Brian Robinson, Anuradha Rao, and Paul Dawson acquired data; Courtney Ferrebee, Jianing Li, Jamie Haywood, Anuradha Rao, Brian Robinson, Rheinallt Jones, Benjamin Hinrichs, and Paul Dawson were responsible for the analysis and interpretation of data; Courtney Ferrebee, Rheinallt Jones, and Paul Dawson drafted the manuscript; Rheinallt Jones and Paul Dawson obtained funding; and Paul Dawson was responsible for study supervision.

Acknowledgments: The authors thank Lou Craddock at the Wake Forest School of Medicine Cancer Genomics Shared Resource for expert technical assistance with the microarray studies, and Dr Neil Anthony at the Emory University Integrated Cellular Imaging Core for assistance and helpful discussions.

Conflicts of interest: The authors disclose no conflicts

Subject:

Research Funding:

This research was funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants DK047987 (P.D.) and DK098391 (R.J.), the Emory University Integrated Cellular Imaging Microscopy Core of the Emory+Children’s Pediatric Research Center and Children’s Healthcare of Atlanta and Emory University’s Pediatric Biomarkers Core

Also supported by a Research Training in Translational Gastroenterology and Hepatology Training grant (National Institutes of Health T32 DK108735 to B.S.R.), and by a Research Supplement to Promote Diversity in Health Related Research from the National Institutes of Health (DK047987S1 to C.B.F.).

Keywords:

  • ARE, anti-oxidant response element
  • Asbt, apical sodium-dependent bile acid transporter
  • CDCA, chenodeoxycholic acid
  • Drosophila
  • FGF, fibroblast growth factor
  • FXR, farnesoid X receptor
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • GFP, green fluorescence protein
  • GSH, reduced glutathione
  • GSSG, oxidized glutathione
  • Ibabp, ileal bile acid binding protein
  • Ileum
  • NEC, necrotizing enterocolitis
  • Neonate
  • Nox, reduced nicotinamide adenine dinucleotide phosphate oxidase
  • Nrf2, nuclear factor (erythroid-derived 2)-like 2
  • Nuclear Factor Erythroid-Derived 2-Like 2
  • Ost, organic solute transporter
  • PBS, phosphate-buffered saline
  • ROS, reactive oxygen species
  • Reactive Oxygen Species
  • TNF, tumor necrosis factor
  • TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling
  • WT, wild type
  • cRNA, complementary RNA
  • mRNA, messenger RNA

Organic Solute Transporter α-β Protects Ileal Enterocytes From Bile Acid–Induced Injury

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Journal Title:

Cellular and Molecular Gastroenterology and Hepatology

Volume:

Volume 5, Number 4

Publisher:

, Pages 499-522

Type of Work:

Article | Final Publisher PDF

Abstract:

Background & Aims: Ileal bile acid absorption is mediated by uptake via the apical sodium-dependent bile acid transporter (ASBT), and export via the basolateral heteromeric organic solute transporter α-β (OSTα-OSTβ). In this study, we investigated the cytotoxic effects of enterocyte bile acid stasis in Ostα-/-mice, including the temporal relationship between intestinal injury and initiation of the enterohepatic circulation of bile acids. Methods: Ileal tissue morphometry, histology, markers of cell proliferation, gene, and protein expression were analyzed in male and female wild-type and Ostα-/-mice at postnatal days 5, 10, 15, 20, and 30. Ostα-/-Asbt-/-mice were generated and analyzed. Bile acid activation of intestinal Nrf2-activated pathways was investigated in Drosophila. Results: As early as day 5, Ostα-/-mice showed significantly increased ileal weight per length, decreased villus height, and increased epithelial cell proliferation. This correlated with premature expression of the Asbt and induction of bile acid–activated farnesoid X receptor target genes in neonatal Ostα-/-mice. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase-1 and Nrf2–anti-oxidant responsive genes were increased significantly in neonatal Ostα-/-mice at these postnatal time points. Bile acids also activated Nrf2 in Drosophila enterocytes and enterocyte-specific knockdown of Nrf2 increased sensitivity of flies to bile acid–induced toxicity. Inactivation of the Asbt prevented the changes in ileal morphology and induction of anti-oxidant response genes in Ostα-/-mice. Conclusions: Early in postnatal development, loss of Ostα leads to bile acid accumulation, oxidative stress, and a restitution response in ileum. In addition to its essential role in maintaining bile acid homeostasis, Ostα-Ostβ functions to protect the ileal epithelium against bile acid–induced injury. NCBI Gene Expression Omnibus: GSE99579.

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© 2018 The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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