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Article

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

by
Dino Šisl
1,2,
Darja Flegar
1,2,
Maša Filipović
1,2,
Petra Turčić
3,
Pavao Planinić
4,
Alan Šućur
1,2,
Nataša Kovačić
1,5,
Danka Grčević
1,2 and
Tomislav Kelava
1,2,*
1
Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
2
Department of Physiology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
3
Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
4
Department of Physiology, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
5
Department of Anatomy, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
*
Author to whom correspondence should be addressed.
Biomedicines 2022, 10(5), 1209; https://doi.org/10.3390/biomedicines10051209
Submission received: 25 April 2022 / Revised: 17 May 2022 / Accepted: 19 May 2022 / Published: 23 May 2022
(This article belongs to the Section Drug Discovery, Development and Delivery)
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Abstract

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.
Keywords: liver fibrosis; tamoxifen; DDC model; cholestatic liver disease liver fibrosis; tamoxifen; DDC model; cholestatic liver disease

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MDPI and ACS Style

Šisl, D.; Flegar, D.; Filipović, M.; Turčić, P.; Planinić, P.; Šućur, A.; Kovačić, N.; Grčević, D.; Kelava, T. Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism. Biomedicines 2022, 10, 1209. https://doi.org/10.3390/biomedicines10051209

AMA Style

Šisl D, Flegar D, Filipović M, Turčić P, Planinić P, Šućur A, Kovačić N, Grčević D, Kelava T. Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism. Biomedicines. 2022; 10(5):1209. https://doi.org/10.3390/biomedicines10051209

Chicago/Turabian Style

Šisl, Dino, Darja Flegar, Maša Filipović, Petra Turčić, Pavao Planinić, Alan Šućur, Nataša Kovačić, Danka Grčević, and Tomislav Kelava. 2022. "Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism" Biomedicines 10, no. 5: 1209. https://doi.org/10.3390/biomedicines10051209

APA Style

Šisl, D., Flegar, D., Filipović, M., Turčić, P., Planinić, P., Šućur, A., Kovačić, N., Grčević, D., & Kelava, T. (2022). Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism. Biomedicines, 10(5), 1209. https://doi.org/10.3390/biomedicines10051209

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