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Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression

Abstract

Bile acid (BA) homeostasis is regulated by the extensive cross-talk between liver and intestine. Many bile-acid-activated signaling pathways have become attractive therapeutic targets for the treatment of metabolic disorders. In this study we investigated the regulatory mechanisms of BA in the intestine. We showed that the BA levels in the gallbladder and faeces were significantly increased, whereas serum BA levels decreased in systemic Krüppel-like factor 9 (Klf9) deficiency (Klf9−/−) mice. These phenotypes were also observed in the intestine-specific Klf9-deleted (Klf9vil−/−) mice. In contrast, BA levels in the gallbladder and faeces were reduced, whereas BA levels in the serum were increased in intestinal Klf9 transgenic (Klf9Rosa26+/+) mice. By using a combination of biochemical, molecular and functional assays, we revealed that Klf9 promoted the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum to enhance BA absorption in the intestine. Reabsorbed BA affected liver BA synthetic enzymes by regulating Fgf15 expression. This study has identified a previously neglected transcriptional pathway that regulates BA homeostasis.

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Fig. 1: Klf9 deletion results in BA dysregulation in enterohepatic circulation.
Fig. 2: Klf9 regulation of BA synthesis has a nonhepatic basis.
Fig. 3: Klf9 affects BA metabolism in the intestine.
Fig. 4: Klf9 induces Asbt expression in the terminal ileum.
Fig. 5: Klf9 overexpression promotes BA reabsorption.
Fig. 6: Changes in small intestine morphology.
Fig. 7: Proposed model of Klf9 induction of BAs absorption.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 81730024 and 81825004), the National Key Research and Development Program of China (2018YFA0800601), the Scientific and Technological Research Project of Xinjiang Production and Construction Corps (grants 2018AB018 and 2021AB028) and the Tianjin Research Innovation Project for Postgraduate Students (2021YJSB259).

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Contributions

YSC, SL, and ML designed research studies. YLZ, YJZ and CYD contributed to the methodology. MLZ and CZW contributed to the investigation. SL, ML, MLZ, SFS, WW, YTF, JNS, JCH, YYF, WQ, JLH YHL provided formal analysis. YSC contributed to the validation. SL and ML wrote the original draft of the manuscript. LZ, JZ, YSC acquired funding.

Corresponding authors

Correspondence to Lu Zhou, Jun Zhang or Yong-sheng Chang.

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The authors declare no competing interests.

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Liu, S., Liu, M., Zhang, Ml. et al. Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression. Acta Pharmacol Sin 43, 2362–2372 (2022). https://doi.org/10.1038/s41401-021-00850-x

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  • DOI: https://doi.org/10.1038/s41401-021-00850-x

Keywords

  • Klf9
  • Asbt
  • bile acid
  • Fgf15

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