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 language | English |
|---|---|
| Pages (from-to) | 601-608 |
| Number of pages | 7 |
| Journal | Biochemical Journal |
| Volume | 387 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 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
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 journal › Article
}
TY - JOUR
T1 - Pregnenolone 16a Carbonitrile Inhibits Rodent Liver Fibrogenesis via PXR-Dependent and PXR-Independent Mechanisms.
AU - Marek, Carylyn
AU - Tucker, Steven John
AU - Konstantinou, Dimitrios
AU - Elrick, Lucy J.
AU - Haefner, Dee
AU - Sigalas, C.
AU - Murray, Graeme Ian
AU - Goodwin, B.
AU - Wright, Matthew Christopher
PY - 2005
Y1 - 2005
N2 - 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.
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.
KW - collagen
KW - fibrosis
KW - liver
KW - pregnane-X receptor
KW - hepatic stellate cell
KW - transdifferentiation
KW - HEPATIC STELLATE CELLS
KW - NUCLEAR RECEPTOR PXR
KW - RAT-LIVER
KW - CARBON-TETRACHLORIDE
KW - CYTOCHROME-P450
KW - INDUCTION
KW - INJURY
KW - FIBROSIS
KW - GENE
KW - REGENERATION
U2 - 10.1042/BJ20041598
DO - 10.1042/BJ20041598
M3 - Article
VL - 387
SP - 601
EP - 608
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 3
ER -