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Research ArticleMetabolism, Transport, and Pharmacogenomics

Serum- and Glucocorticoid-Regulated Kinase 2 Determines Drug-Activated Pregnane X Receptor to Induce Gluconeogenesis in Human Liver Cells

Saki Gotoh and Masahiko Negishi
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 131-140; DOI: https://doi.org/10.1124/jpet.113.209379
Saki Gotoh
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Masahiko Negishi
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Abstract

Drug activation of the human nuclear pregnane X receptor (PXR) induced gluconeogenic genes and increased glucose production. In this study, we have determined that serum- and glucocorticoid-regulated kinase 2 (SGK2) is an essential factor that mediates this PXR-regulated glucose 6-phosphatase (G6Pase) induction and glucose production. Both SGK2 and G6Pase mRNAs were increased in rifampicin-treated HepG2 cells stably expressing human PXR. Reporter and chromatin immunoprecipitation assays delineated PXR activation of the SGK2 gene to a distal and proximal DNA sequence within its promoter: distal PXR response element (−2587/−2209) and proximal PXR response element (−115/−75), respectively. Small interfering RNA (siRNA) knockdown of SGK2 severely attenuated PXR-regulated induction of G6Pase as well as glucose production. SGK2 constitutes an insulin-independent signal pathway to regulate gluconeogenesis because siRNA knockdown of the insulin-responsive transcription factor forkhead box protein O1 did not affect rifampicin induction of G6Pase. Rifampicin treatment of two different samples of human primary hepatocytes revealed that PXR induces G6Pase in the presence of high levels of SGK2, whereas PXR represses G6Pase in its absence. Mediating PXR activation of the G6Pase gene is the first biological role found for hepatic SGK2 and might have therapeutic implications for side effects, such as diabetes, caused by drugs that activate PXR.

Footnotes

    • Received September 4, 2013.
    • Accepted November 5, 2013.
  • This work was supported by the Intramural Research Program of National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01ES1005-01].

  • dx.doi.org/10.1124/jpet.113.209379.

  • Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleMetabolism, Transport, and Pharmacogenomics

SGK2 Determines Drug-Activated PXR to Induce Gluconeogenesis

Saki Gotoh and Masahiko Negishi
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 131-140; DOI: https://doi.org/10.1124/jpet.113.209379

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Research ArticleMetabolism, Transport, and Pharmacogenomics

SGK2 Determines Drug-Activated PXR to Induce Gluconeogenesis

Saki Gotoh and Masahiko Negishi
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 131-140; DOI: https://doi.org/10.1124/jpet.113.209379
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