Pregnenolone-16α-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms
Open accessAbstract
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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The PXR agonist is associated with inhibition of fibrogenesis in rodent animal models via PXR dependent and independent pathways.
“The pregnane X receptor (PXR) agonist is also seen as a potential target for anti-fibrotic therapy.It was associated with an inhibition of fibrogenesis in rodent animal models via PXR dependent and independent pathways.[193]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [193]
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- Authors
- MAREK, C. J., TUCKER, S. J., KONSTANTINOU, D. K., ELRICK, L. J., HAEFNER, D., SIGALAS, C., MURRAY, G. I., GOODWIN, B., & WRIGHT, M. C.
- Affiliations
- University of Aberdeen (GB)
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, U.K.
- GlaxoSmithKline (United States) (US)
- Corresponding author
- HAEFNER, Dee
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2005-04-26
- Volume
- 387
- Issue
- 3
- Pages
- 601-608
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1134989
- OpenAlex
- W2081670575
- Cited by
- 89
- References
- 40
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 7 · 2016: 2 · 2015: 4 · 2013: 7 · 2012: 3
- FWCI
- 4.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (068879)
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- pregnane X receptor, pregnenolone-16α-carbonitrile, liver fibrosis, hepatic stellate cells, carbon tetrachloride hepatotoxicity, antifibrotic effect
- MeSH terms
- Pregnane X Receptor, Animals, Carbon Tetrachloride, Liver Cirrhosis, Male, Pregnenolone Carbonitrile, Receptors, Steroid, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Hepatocytes, Mice, Rats
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