Glucocorticoid signaling and lipid metabolism disturbances in the liver of rats treated with 5α-dihydrotestosterone in an animal model of polycystic ovary syndrome

doi:10.1007/s12020-020-02600-1

. 2021 May;72(2):562-572.

doi: 10.1007/s12020-020-02600-1. Epub 2021 Jan 15.

Glucocorticoid signaling and lipid metabolism disturbances in the liver of rats treated with 5α-dihydrotestosterone in an animal model of polycystic ovary syndrome

Danijela Vojnović Milutinović¹, Ana Teofilović¹, Nataša Veličković¹, Jelena Brkljačić¹, Sanja Jelača², Ana Djordjevic¹, Djuro Macut³

Affiliations

¹ Department of Biochemistry, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 142 Despot Stefan Blvd., 11000, Belgrade, Serbia.
² Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 142 Despot Stefan Blvd., 11000, Belgrade, Serbia.
³ Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotića 13, 11000, Belgrade, Serbia. djmacut@gmail.com.

PMID: 33449293
DOI: 10.1007/s12020-020-02600-1

Glucocorticoid signaling and lipid metabolism disturbances in the liver of rats treated with 5α-dihydrotestosterone in an animal model of polycystic ovary syndrome

Danijela Vojnović Milutinović et al. Endocrine. 2021 May.

. 2021 May;72(2):562-572.

doi: 10.1007/s12020-020-02600-1. Epub 2021 Jan 15.

Authors

Danijela Vojnović Milutinović¹, Ana Teofilović¹, Nataša Veličković¹, Jelena Brkljačić¹, Sanja Jelača², Ana Djordjevic¹, Djuro Macut³

Affiliations

¹ Department of Biochemistry, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 142 Despot Stefan Blvd., 11000, Belgrade, Serbia.
² Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, 142 Despot Stefan Blvd., 11000, Belgrade, Serbia.
³ Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotića 13, 11000, Belgrade, Serbia. djmacut@gmail.com.

PMID: 33449293
DOI: 10.1007/s12020-020-02600-1

Abstract

Purpose: Polycystic ovary syndrome (PCOS) is a complex reproductive disorder often associated with obesity, insulin resistance, and dyslipidemia. Hormonal changes in PCOS may also include altered glucocorticoid signaling. Our aim was to examine whether alterations in hepatic glucocorticoid signaling are associated with disturbances of glucose and lipid metabolism in animal model of PCOS.

Methods: Female rats, 3 weeks old, were subcutaneously implanted with 5α-dihydrotestosterone (DHT) or placebo pellets for 90 days to induce PCOS. Expression of 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) and A-ring reductases (5α and 5β), as well as intracellular distribution of glucocorticoid receptor (GR) and expression of its regulated genes were examined in the liver. Proteins of hepatic lipid and carbohydrate metabolism and markers of inflammation were also assessed.

Results: DHT treatment induced increase in body and liver mass, as well as in triglycerides and free fatty acids levels in plasma. Elevation of 11βHSD1 and reduction of 5α-reductase expression was observed together with increased hepatic corticosterone concentration and nuclear GR activation. Induced expression of Krüppel-like factor 15 and decreased expression of genes for proinflammatory cytokines and de novo lipogenesis (DNL) were detected in the liver of DHT-treated rats, while DNL regulators and proinflammatory markers were not changed. However, increased mRNA levels of stearoyl-CoA desaturase and apolipoprotein B were observed in DHT animals.

Conclusions: DHT treatment stimulated hepatic glucocorticoid prereceptor metabolism through increased corticosterone availability which is associated with enhanced GR activation. This does not affect gluconeogenesis and DNL, but could be linked to stimulated triglyceride synthesis and hypertriglyceridemia.

Keywords: 5α-Dihydrotestosterone; Glucocorticoids; Liver; Polycystic ovary syndrome; Triglycerides.

PubMed Disclaimer

Cited by

Untargeted metabolomics for acute intra-abdominal infection diagnosis in serum and urine using UHPLC-TripleTOF MS.
Dong Z, Zhang S, Zhang H, Zhao D, Pan Z, Wang D. Dong Z, et al. Front Mol Biosci. 2025 May 8;12:1534102. doi: 10.3389/fmolb.2025.1534102. eCollection 2025. Front Mol Biosci. 2025. PMID: 40406622 Free PMC article.
Thrombosis and Anticoagulation Therapy in Systemic Lupus Erythematosus.
Yuan W, Guan F. Yuan W, et al. Autoimmune Dis. 2022 Jun 27;2022:3208037. doi: 10.1155/2022/3208037. eCollection 2022. Autoimmune Dis. 2022. PMID: 35795725 Free PMC article. Review.
Effects of letrozole combined with ethinylestradiol and cyproterone acetate tablets on serum sex hormones and lipid metabolism in patients with polycystic ovary syndrome.
Lu K, Li N, Zhang M, Lin J, Chen J. Lu K, et al. Am J Transl Res. 2023 Feb 15;15(2):1271-1280. eCollection 2023. Am J Transl Res. 2023. PMID: 36915753 Free PMC article.
Genes in loci genetically associated with polycystic ovary syndrome are dynamically expressed in human fetal gonadal, metabolic and brain tissues.
Azumah R, Hummitzsch K, Anderson RA, Rodgers RJ. Azumah R, et al. Front Endocrinol (Lausanne). 2023 May 8;14:1149473. doi: 10.3389/fendo.2023.1149473. eCollection 2023. Front Endocrinol (Lausanne). 2023. PMID: 37223019 Free PMC article.
Maternal nutrient metabolism in the liver during pregnancy.
Fang H, Li Q, Wang H, Ren Y, Zhang L, Yang L. Fang H, et al. Front Endocrinol (Lausanne). 2024 Mar 20;15:1295677. doi: 10.3389/fendo.2024.1295677. eCollection 2024. Front Endocrinol (Lausanne). 2024. PMID: 38572473 Free PMC article. Review.

See all "Cited by" articles

References

1. G. Conway, D. Dewailly, E. Diamanti-Kandarakis, H.F. Escobar-Morreale, S. Franks, A. Gambineri, F. Kelestimur, D. Macut, D. Micic, R. Dewailly, M. Pfeifer, D. Pignatelli, M. Pugeat, B.O. Yildiz, E. P. S. I. Group, The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur. J. Endocrinol. 171(4), P1–P29 (2014). https://doi.org/10.1530/EJE-14-0253 - DOI - PubMed
1. H. Jones, V.S. Sprung, C.J. Pugh, C. Daousi, A. Irwin, N. Aziz, V.L. Adams, E.L. Thomas, J.D. Bell, G.J. Kemp, D.J. Cuthbertson, Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J. Clin. Endocrinol. Metab. 97(10), 3709–3716 (2012). https://doi.org/10.1210/jc.2012-1382 - DOI - PubMed
1. D. Macut, J. Bjekić-Macut, S. Livadas, O. Stanojlović, D. Hrncic, A. Rašić-Marković, D. Vojnović Milutinović, V. Mladenović, Z. Andrić, Nonalcoholic fatty liver disease in patients with polycystic ovary syndrome. Curr. Pharm. Des. 24(38), 4593–4597 (2018). https://doi.org/10.2174/1381612825666190117100751 - DOI - PubMed
1. A.L.L. Rocha, L.C. Faria, T.C.M. Guimaraes, G.V. Moreira, A.L. Candido, C.A. Couto, F.M. Reis, Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J. Endocrinol. Investig. 40(12), 1279–1288 (2017). https://doi.org/10.1007/s40618-017-0708-9 - DOI
1. J.M. Hazlehurst, J.W. Tomlinson, Non-alcoholic fatty liver disease in common endocrine disorders. Eur. J. Endocrinol. 169(2), R27–R37 (2013). https://doi.org/10.1530/EJE-13-0296 - DOI - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

LinkOut - more resources

Full Text Sources
- Springer
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information

[1] G. Conway, D. Dewailly, E. Diamanti-Kandarakis, H.F. Escobar-Morreale, S. Franks, A. Gambineri, F. Kelestimur, D. Macut, D. Micic, R. Dewailly, M. Pfeifer, D. Pignatelli, M. Pugeat, B.O. Yildiz, E. P. S. I. Group, The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur. J. Endocrinol. 171(4), P1–P29 (2014). https://doi.org/10.1530/EJE-14-0253 - DOI - PubMed

[2] G. Conway, D. Dewailly, E. Diamanti-Kandarakis, H.F. Escobar-Morreale, S. Franks, A. Gambineri, F. Kelestimur, D. Macut, D. Micic, R. Dewailly, M. Pfeifer, D. Pignatelli, M. Pugeat, B.O. Yildiz, E. P. S. I. Group, The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur. J. Endocrinol. 171(4), P1–P29 (2014). https://doi.org/10.1530/EJE-14-0253 - DOI - PubMed

[3] H. Jones, V.S. Sprung, C.J. Pugh, C. Daousi, A. Irwin, N. Aziz, V.L. Adams, E.L. Thomas, J.D. Bell, G.J. Kemp, D.J. Cuthbertson, Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J. Clin. Endocrinol. Metab. 97(10), 3709–3716 (2012). https://doi.org/10.1210/jc.2012-1382 - DOI - PubMed

[4] H. Jones, V.S. Sprung, C.J. Pugh, C. Daousi, A. Irwin, N. Aziz, V.L. Adams, E.L. Thomas, J.D. Bell, G.J. Kemp, D.J. Cuthbertson, Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J. Clin. Endocrinol. Metab. 97(10), 3709–3716 (2012). https://doi.org/10.1210/jc.2012-1382 - DOI - PubMed

[5] D. Macut, J. Bjekić-Macut, S. Livadas, O. Stanojlović, D. Hrncic, A. Rašić-Marković, D. Vojnović Milutinović, V. Mladenović, Z. Andrić, Nonalcoholic fatty liver disease in patients with polycystic ovary syndrome. Curr. Pharm. Des. 24(38), 4593–4597 (2018). https://doi.org/10.2174/1381612825666190117100751 - DOI - PubMed

[6] D. Macut, J. Bjekić-Macut, S. Livadas, O. Stanojlović, D. Hrncic, A. Rašić-Marković, D. Vojnović Milutinović, V. Mladenović, Z. Andrić, Nonalcoholic fatty liver disease in patients with polycystic ovary syndrome. Curr. Pharm. Des. 24(38), 4593–4597 (2018). https://doi.org/10.2174/1381612825666190117100751 - DOI - PubMed

[7] A.L.L. Rocha, L.C. Faria, T.C.M. Guimaraes, G.V. Moreira, A.L. Candido, C.A. Couto, F.M. Reis, Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J. Endocrinol. Investig. 40(12), 1279–1288 (2017). https://doi.org/10.1007/s40618-017-0708-9 - DOI

[8] A.L.L. Rocha, L.C. Faria, T.C.M. Guimaraes, G.V. Moreira, A.L. Candido, C.A. Couto, F.M. Reis, Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J. Endocrinol. Investig. 40(12), 1279–1288 (2017). https://doi.org/10.1007/s40618-017-0708-9 - DOI

[9] J.M. Hazlehurst, J.W. Tomlinson, Non-alcoholic fatty liver disease in common endocrine disorders. Eur. J. Endocrinol. 169(2), R27–R37 (2013). https://doi.org/10.1530/EJE-13-0296 - DOI - PubMed

[10] J.M. Hazlehurst, J.W. Tomlinson, Non-alcoholic fatty liver disease in common endocrine disorders. Eur. J. Endocrinol. 169(2), R27–R37 (2013). https://doi.org/10.1530/EJE-13-0296 - DOI - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Glucocorticoid signaling and lipid metabolism disturbances in the liver of rats treated with 5α-dihydrotestosterone in an animal model of polycystic ovary syndrome

Affiliations

Glucocorticoid signaling and lipid metabolism disturbances in the liver of rats treated with 5α-dihydrotestosterone in an animal model of polycystic ovary syndrome

Authors

Affiliations

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical