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KLF15 regulates endobiotic and xenobiotic metabolism

Nature Metabolism volume 1, pages 422–430 (2019)Cite this article

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Abstract

Hepatic metabolism and elimination of endobiotics (for example, steroids, bile acids) and xenobiotics (for example, drugs, toxins) is essential for health. While the enzymatic (termed phase I–II) and transport machinery (termed phase III) controlling endobiotic and xenobiotic metabolism (EXM) is known, understanding of molecular nodal points that coordinate EXM function in physiology and disease remains incomplete. Here we show that the transcription factor Kruppel-like factor 15 (KLF15) regulates all three phases of the EXM system by direct and indirect pathways. Unbiased transcriptomic analyses coupled with validation studies in cells, human tissues, and animals, support direct transcriptional control of the EXM machinery by KLF15. Liver-specific deficiency of KLF15 (Li-KO) results in altered expression of numerous phase I–III targets, and renders animals resistant to the pathologic effects of bile acid and acetaminophen toxicity. Furthermore, Li-KO mice demonstrate enhanced degradation and elimination of endogenous steroid hormones, such as testosterone and glucocorticoid, resulting in reduced male fertility and blood glucose levels, respectively. Viral reconstitution of hepatic KLF15 expression in Li-KO mice reverses these phenotypes. Our observations identify a previously unappreciated transcriptional pathway regulating metabolism and elimination of endobiotics and xenobiotics.

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Fig. 1: Bile acids and acetaminophen inhibit hepatic KLF15 through PXR activation.
Fig. 2: Hepatic KLF15 deficiency resists BDL-induced BA toxicity.
Fig. 3: Depletion of hepatic KLF15 robustly resists acetaminophen overdose-induced toxicity and acute liver failure.
Fig. 4: Hepatic KLF15 deficiency enhances EXM biotransformation and elimination of testosterone and corticosterone leading to reduced reproduction and blood glucose.

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Data availability

RNA-seq data have been deposited in Gene Expression Omnibus (GEO) under accession code GSE126762.

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Acknowledgements

We thank the Liver Tissue Cell Distribution System at University of Minnesota for providing liver tissues. We acknowledge the University Hospitals Laboratory Core for the mouse blood tests. We wish to thank J. Chiang (Northeast Ohio Medical University) for his critical advice. We also thank H.-Y. Kao for human NRF2 plasmid. This research is supported by grants 1R35HL135789, 1R01DK111468-01, and AHA EIA14370009 (to M.K.J.) and T32GM007250 and F30HL139014 (to D.R.S.). We thank S. Haldar for sharing unpublished ChIP-seq data.

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Authors and Affiliations

  1. Case Cardiovascular Research Institute Case Western Reserve University, Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Shuxin Han, Preeti Pathak, David R. Sweet, Rongli Zhang, Huiyun Gao, Nisha Jain, Erik H. Koritzinsky, Keiichiro Matoba, Daniel I. Simon & Mukesh K. Jain

  2. Department of Physiology, Case Western Reserve University, Cleveland, OH, USA

    Jonathan W. Ray

  3. Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA

    Jonathan W. Ray

  4. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    David R. Sweet

  5. Institute for Transformative Molecular Medicine Case Western Reserve University, Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Rongli Zhang

  6. Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan

    Keiichiro Matoba

  7. Cleveland School of Science and Medicine at John Hay Campus, Cleveland, OH, USA

    Weixiong Xu

  8. College of Arts and Sciences, Ohio State University, Columbus, OH, USA

    Weixiong Xu

  9. Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA

    E. Ricky Chan

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Contributions

S.H. and M.K.J. conceived the project. S.H. and J.W.R. performed most experiments. S.H. and M.K.J. designed the research. S.H., J.W.R., N.J., and M.K.J. co-wrote the manuscript. P.P. performed EMSA. R.Z. contributed to bile duct ligation and tail-vein injection studies. D.R.S. co-wrote the manuscript, and contributed to RNA isolation for the RNA-seq experiment and Fig. 4o. H.G. and D.I.S. contributed to Fig. 4l,m. W.X. contributed to several in vitro experiments. E.H.K. performed transfection and luciferase reporter assays. E.R.C. analysed the RNA-seq data and contributed to Fig. 1a and Supplementary Fig. 1b.

Corresponding authors

Correspondence to Shuxin Han or Mukesh K. Jain.

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Competing interests

The authors declare no competing interests. A patent based on this manuscript has been submitted. The patent applicant is Case Western Reserve University. The inventors are Shuxin Han and Mukesh K. Jain. The application number is US Provisional Patent Application No. 62/810,080. The status of the application is pending. The specific aspect of the manuscript covered in the patent application is ‘Transient Inhibition of KLF15 Resists Liver Injury’.

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Han, S., Ray, J.W., Pathak, P. et al. KLF15 regulates endobiotic and xenobiotic metabolism. Nat Metab 1, 422–430 (2019). https://doi.org/10.1038/s42255-019-0054-7

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