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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/10/5/1209 |
| _version_ | 1797501289217654784 |
|---|---|
| author | Dino Šisl Darja Flegar Maša Filipović Petra Turčić Pavao Planinić Alan Šućur Nataša Kovačić Danka Grčević Tomislav Kelava |
| author_facet | Dino Šisl Darja Flegar Maša Filipović Petra Turčić Pavao Planinić Alan Šućur Nataša Kovačić Danka Grčević Tomislav Kelava |
| author_sort | Dino Šisl |
| collection | DOAJ |
| 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, <i>p</i> < 0.001 and <i>p</i> < 0.01, respectively) and by lower hydroxyproline content. The finding was further confirmed by qPCR analysis, which showed a lower expression of genes for <i>Col1a1</i>, <i>Acta2</i>, <i>Sox9</i>, <i>Pdgf</i>, and <i>Krt19</i>, 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 <i>Il6</i> (<i>p</i> < 0.01 and <i>p</i> < 0.001 in male and female mice, respectively) and <i>Tgfβ</i> (<i>p</i> < 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. |
| first_indexed | 2024-03-10T03:16:15Z |
| format | Article |
| id | doaj.art-1c77200d84614a6eb792ca06c3bc8aaa |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T03:16:15Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-1c77200d84614a6eb792ca06c3bc8aaa2023-11-23T10:12:39ZengMDPI AGBiomedicines2227-90592022-05-01105120910.3390/biomedicines10051209Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective MechanismDino Šisl0Darja Flegar1Maša Filipović2Petra Turčić3Pavao Planinić4Alan Šućur5Nataša Kovačić6Danka Grčević7Tomislav Kelava8Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, CroatiaLaboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, CroatiaLaboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, CroatiaDepartment of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, CroatiaDepartment of Physiology, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and HerzegovinaLaboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, CroatiaLaboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, CroatiaLaboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, CroatiaLaboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, CroatiaThe 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, <i>p</i> < 0.001 and <i>p</i> < 0.01, respectively) and by lower hydroxyproline content. The finding was further confirmed by qPCR analysis, which showed a lower expression of genes for <i>Col1a1</i>, <i>Acta2</i>, <i>Sox9</i>, <i>Pdgf</i>, and <i>Krt19</i>, 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 <i>Il6</i> (<i>p</i> < 0.01 and <i>p</i> < 0.001 in male and female mice, respectively) and <i>Tgfβ</i> (<i>p</i> < 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.https://www.mdpi.com/2227-9059/10/5/1209liver fibrosistamoxifenDDC modelcholestatic liver disease |
| spellingShingle | Dino Šisl Darja Flegar Maša Filipović Petra Turčić Pavao Planinić Alan Šućur Nataša Kovačić Danka Grčević Tomislav Kelava Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism Biomedicines liver fibrosis tamoxifen DDC model cholestatic liver disease |
| 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 | liver fibrosis tamoxifen DDC model cholestatic liver disease |
| url | https://www.mdpi.com/2227-9059/10/5/1209 |
| work_keys_str_mv | AT dinosisl tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT darjaflegar tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT masafilipovic tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT petraturcic tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT pavaoplaninic tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT alansucur tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT natasakovacic tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT dankagrcevic tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism AT tomislavkelava tamoxifenamelioratescholestaticliverfibrosisinmiceupregulationoftgfbandil6isapotentialprotectivemechanism |