Pregnenolone 16a Carbonitrile Inhibits Rodent Liver Fibrogenesis via PXR-Dependent and PXR-Independent Mechanisms.

Carylyn Marek, Steven John Tucker, Dimitrios Konstantinou, Lucy J. Elrick, Dee Haefner, C. Sigalas, Graeme Ian Murray, B. Goodwin, Matthew Christopher Wright

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16α-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR-/-) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR-/--derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.

Original languageEnglish
Pages (from-to)601-608
Number of pages7
JournalBiochemical Journal
Volume387
Issue number3
DOIs
Publication statusPublished - 2005

Keywords

  • collagen
  • fibrosis
  • liver
  • pregnane-X receptor
  • hepatic stellate cell
  • transdifferentiation
  • HEPATIC STELLATE CELLS
  • NUCLEAR RECEPTOR PXR
  • RAT-LIVER
  • CARBON-TETRACHLORIDE
  • CYTOCHROME-P450
  • INDUCTION
  • INJURY
  • FIBROSIS
  • GENE
  • REGENERATION

Cite this

Marek, C., Tucker, S. J., Konstantinou, D., Elrick, L. J., Haefner, D., Sigalas, C., ... Wright, M. C. (2005). Pregnenolone 16a Carbonitrile Inhibits Rodent Liver Fibrogenesis via PXR-Dependent and PXR-Independent Mechanisms. Biochemical Journal, 387(3), 601-608. https://doi.org/10.1042/BJ20041598

Pregnenolone 16a Carbonitrile Inhibits Rodent Liver Fibrogenesis via PXR-Dependent and PXR-Independent Mechanisms. / Marek, Carylyn; Tucker, Steven John; Konstantinou, Dimitrios; Elrick, Lucy J.; Haefner, Dee; Sigalas, C.; Murray, Graeme Ian; Goodwin, B.; Wright, Matthew Christopher.

In: Biochemical Journal, Vol. 387, No. 3, 2005, p. 601-608.

Research output: Contribution to journalArticle

Marek, C, Tucker, SJ, Konstantinou, D, Elrick, LJ, Haefner, D, Sigalas, C, Murray, GI, Goodwin, B & Wright, MC 2005, 'Pregnenolone 16a Carbonitrile Inhibits Rodent Liver Fibrogenesis via PXR-Dependent and PXR-Independent Mechanisms.', Biochemical Journal, vol. 387, no. 3, pp. 601-608. https://doi.org/10.1042/BJ20041598
Marek, Carylyn ; Tucker, Steven John ; Konstantinou, Dimitrios ; Elrick, Lucy J. ; Haefner, Dee ; Sigalas, C. ; Murray, Graeme Ian ; Goodwin, B. ; Wright, Matthew Christopher. / Pregnenolone 16a Carbonitrile Inhibits Rodent Liver Fibrogenesis via PXR-Dependent and PXR-Independent Mechanisms. In: Biochemical Journal. 2005 ; Vol. 387, No. 3. pp. 601-608.
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abstract = "The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16α-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR-/-) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR-/--derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.",
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AB - The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16α-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR-/-) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR-/--derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.

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KW - FIBROSIS

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KW - REGENERATION

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