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Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine
  1. Eva Beuling1,
  2. Ilona M Kerkhof1,
  3. Grace A Nicksa2,
  4. Michael J Giuffrida2,
  5. Jamie Haywood3,
  6. Daniel J aan de Kerk1,
  7. Christina M Piaseckyj1,
  8. William T Pu4,
  9. Terry L Buchmiller2,
  10. Paul A Dawson3,
  11. Stephen D Krasinski1,5
  1. 1Division of Gastroenterology and Nutrition, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts, USA
  2. 2Department of Surgery, Children's Hospital Boston, Boston, Massachusetts, USA
  3. 3Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
  4. 4Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts, USA
  5. 5Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, USA
  1. Correspondence to Dr Stephen D Krasinski, GI/Cell Biology, EN 720, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA; stephen.krasinski{at}childrens.harvard.edu

Abstract

Background and aims The transcription factor GATA4 is expressed throughout most of the small intestine except distal ileum, and restricts expression of the apical sodium-dependent bile acid transporter (ASBT), the rate-limiting intestinal bile acid transporter, to distal ileum. The hypothesis was tested that reduction of GATA4 activity in mouse small intestine results in an induction of bile acid transport in proximal small intestine sufficient to restore bile acid absorption and homeostasis after ileocaecal resection (ICR).

Methods Bile acid homeostasis was characterised in non-surgical, sham or ICR mice using two recombinant Gata4 models in which Asbt expression is induced to different levels.

Results Reduction of intestinal GATA4 activity resulted in an induction of ASBT expression, bile acid absorption and expression of bile acid-responsive genes in proximal small intestine, and a reduction of luminal bile acids in distal small intestine. While faecal bile acid excretion and bile acid pool size remained unchanged, the bile acid pool became more hydrophilic due to a relative increase in tauro-β-muricholate absorption. Furthermore, proximal induction of Asbt in both Gata4 mutant models corrected ICR-associated bile acid malabsorption, reversing the decrease in bile acid pool size and increase in faecal bile acid excretion and hepatic cholesterol 7α-hydroxylase expression.

Conclusions Reduction of intestinal GATA4 activity induces bile acid absorption in proximal small intestine without inducing major changes in bile acid homeostasis. This induction is sufficient to correct bile acid malabsorption caused by ICR in mice.

  • ASBT
  • bile acid (mal)absorption
  • bile acid metabolism
  • gene mutation
  • ileocaecal resection
  • intestinal Gata4 deletion
  • intestinal gene regulation
  • intestinal malabsorption
  • small intestinal absorption

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Footnotes

  • Funding This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK-061382 (SDK) and R01-DK-047987 (PAD), a Harvard Digestive Disease Center grant 5P30-DK-34854, the Nutricia Research Foundation (EB), the Foundation De Drie Lichten (EB) and the Foundation Doctor Catharine van Tussenbroek (EB) in The Netherlands.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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