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Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism

The available treatments for cholestatic liver fibrosis are limited, and the disease often progresses to liver cirrhosis. Tamoxifen is a selective modulator of estrogen receptors, commonly used in breast cancer therapy. A recent in vitro study showed that tamoxifen deactivates hepatic stellate cells...

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Autores principales: Šisl, Dino, Flegar, Darja, Filipović, Maša, Turčić, Petra, Planinić, Pavao, Šućur, Alan, Kovačić, Nataša, Grčević, Danka, Kelava, Tomislav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138605/
https://www.ncbi.nlm.nih.gov/pubmed/35625945
http://dx.doi.org/10.3390/biomedicines10051209
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author Šisl, Dino
Flegar, Darja
Filipović, Maša
Turčić, Petra
Planinić, Pavao
Šućur, Alan
Kovačić, Nataša
Grčević, Danka
Kelava, Tomislav
author_facet Šisl, Dino
Flegar, Darja
Filipović, Maša
Turčić, Petra
Planinić, Pavao
Šućur, Alan
Kovačić, Nataša
Grčević, Danka
Kelava, Tomislav
author_sort Šisl, Dino
collection PubMed
description The available treatments for cholestatic liver fibrosis are limited, and the disease often progresses to liver cirrhosis. Tamoxifen is a selective modulator of estrogen receptors, commonly used in breast cancer therapy. A recent in vitro study showed that tamoxifen deactivates hepatic stellate cells, suggesting its potential as an antifibrotic therapeutic, but its effects in vivo remain poorly investigated. In the present study, we show that tamoxifen protects against the cholestatic fibrosis induced by a diet supplemented with 0.025% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Mice fed with a DDC-supplemented diet for four weeks and treated with tamoxifen developed a significantly milder degree of liver fibrosis than vehicle-treated mice, as evidenced by a lower percentage of Sirius red-stained area (60.4% decrease in stained area in male and 42% decrease in female mice, p < 0.001 and p < 0.01, respectively) and by lower hydroxyproline content. The finding was further confirmed by qPCR analysis, which showed a lower expression of genes for Col1a1, Acta2, Sox9, Pdgf, and Krt19, indicating the inhibitory effect on hepatic stellate cells, collagen production, and biliary duct proliferation. The degree of protection was similar in male and female mice. Tamoxifen per se, injected into standard-diet-fed mice, increased the expression of genes for Il6 (p < 0.01 and p < 0.001 in male and female mice, respectively) and Tgfβ (p < 0.01 for both sexes), and had no adverse effects. We showed that tamoxifen sex-independently protects against cholestatic DDC-induced liver fibrosis. The increased expression of Il6 and Tgfβ seems to be a plausible protective mechanism that should be the primary focus of further research.
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spelling pubmed-91386052022-05-28 Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism Šisl, Dino Flegar, Darja Filipović, Maša Turčić, Petra Planinić, Pavao Šućur, Alan Kovačić, Nataša Grčević, Danka Kelava, Tomislav Biomedicines Article The available treatments for cholestatic liver fibrosis are limited, and the disease often progresses to liver cirrhosis. Tamoxifen is a selective modulator of estrogen receptors, commonly used in breast cancer therapy. A recent in vitro study showed that tamoxifen deactivates hepatic stellate cells, suggesting its potential as an antifibrotic therapeutic, but its effects in vivo remain poorly investigated. In the present study, we show that tamoxifen protects against the cholestatic fibrosis induced by a diet supplemented with 0.025% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Mice fed with a DDC-supplemented diet for four weeks and treated with tamoxifen developed a significantly milder degree of liver fibrosis than vehicle-treated mice, as evidenced by a lower percentage of Sirius red-stained area (60.4% decrease in stained area in male and 42% decrease in female mice, p < 0.001 and p < 0.01, respectively) and by lower hydroxyproline content. The finding was further confirmed by qPCR analysis, which showed a lower expression of genes for Col1a1, Acta2, Sox9, Pdgf, and Krt19, indicating the inhibitory effect on hepatic stellate cells, collagen production, and biliary duct proliferation. The degree of protection was similar in male and female mice. Tamoxifen per se, injected into standard-diet-fed mice, increased the expression of genes for Il6 (p < 0.01 and p < 0.001 in male and female mice, respectively) and Tgfβ (p < 0.01 for both sexes), and had no adverse effects. We showed that tamoxifen sex-independently protects against cholestatic DDC-induced liver fibrosis. The increased expression of Il6 and Tgfβ seems to be a plausible protective mechanism that should be the primary focus of further research. MDPI 2022-05-23 /pmc/articles/PMC9138605/ /pubmed/35625945 http://dx.doi.org/10.3390/biomedicines10051209 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Šisl, Dino
Flegar, Darja
Filipović, Maša
Turčić, Petra
Planinić, Pavao
Šućur, Alan
Kovačić, Nataša
Grčević, Danka
Kelava, Tomislav
Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
title Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
title_full Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
title_fullStr Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
title_full_unstemmed Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
title_short Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
title_sort tamoxifen ameliorates cholestatic liver fibrosis in mice: upregulation of tgfβ and il6 is a potential protective mechanism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138605/
https://www.ncbi.nlm.nih.gov/pubmed/35625945
http://dx.doi.org/10.3390/biomedicines10051209
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