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