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KLF15 regulates endobiotic and xenobiotic metabolism
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Journal Article
KLF15 regulates endobiotic and xenobiotic metabolism
2019
Overview
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.
The transcription factor Klf15 controls various metabolic processes, including bile acid synthesis. Here the authors show that Klf15 acts as an upstream regulator of xenobiotic and endobiotic metabolism by controlling expression of a variety of phase I–III metabolic genes via direct and indirect mechanisms.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
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/ Acids
/ Animals
/ Bile
/ Biomedical and Life Sciences
/ Electrophoretic Mobility Shift Assay
/ Genes
/ Humans
/ Kruppel-Like Transcription Factors - genetics
/ Kruppel-Like Transcription Factors - physiology
/ Letter
/ Liver
/ Male
/ Mice
/ Proteins
/ Toxicity
