Preview

Experimental and Clinical Gastroenterology

Advanced search

Common pathogenetic mechanisms of non-alcoholic fatty liver disease and polycystic ovary syndrome

https://doi.org/10.31146/1682-8658-ecg-230-10-90-97

Abstract

The prevalence of polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD) has a clear association with each other, and the presence of one disease increases the risks of developing the other, which must be taken into account when comprehensively assessing the patient’s condition. Both diseases increase the risk of developing socially significant diseases associated with decreased life expectancy, such as type 2 diabetes mellitus and cardiovascular diseases. The purpose of this review was to summarize current data on the prevalence and pathophysiology of NAFLD in PCOS. Publications on PCOS and NAFLD were analyzed using a search of the Russian Science Citation Index, MEDLINE and Pub Med over the past 10 years, using the keywords: “PCOS”, “NAFLD”, “insulin resistance”, “hyperandrogenemia”. The author of the review included the most interesting works, covering the problem broadly and comprehensively. The analysis of the literature showed that the pathogenesis of both PCOS and NAFLD involves factors such as hyperandrogenemia, insulin resistance with compensatory hyperinsulinemia (involving in the process of metabolic dysregulation of all “classical” insulin target organs, including skeletal muscles), mitochondrial dysfunction and intestinal dysbiosis. The pathophysiological process of the formation of PCOS and NAFLD is characterized by the formation of “vicious” circles, when a violation of one link in the pathogenesis activates other links, aggravating and maintaining primary deviations. This indicates that it is necessary to search for complex, non-trivial approaches to the diagnosis and treatment of these diseases, using drugs from various groups, including insulin sensors, metabiotics, antioxidants and hepatoprotectors. The role of each drug have to be assessed in clinical trials.

About the Author

I. A. Ilovayskaya
Moscow Region Research and Clinical Institute n. a. M.F. Vladimirskiy
Russian Federation


References

1. Lazebnik L.B., Golovanova E.V., Turkina S.V. et al. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. Experimental and Clinical Gastroenterology. 2021;1(1):4-52. (in Russ.) doi: 10.31146/1682-8658-ecg-185-1-4-52.

2. Younossi Z.M., Koenig A.B., Abdelatif D. et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi: 10.1002/hep.28431.

3. Quek J., Chan K.E., Wong Z.Y. et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(1):20-30. doi: 10.1016/S2468-1253(22)00317-X

4. Watt M.J., Miotto P.M., De Nardo W., Montgomery M.K. The Liver as an Endocrine Organ - Linking NAFLD and Insulin Resistance. Endocr Rev. 2019;40(5):1367-1393. doi: 10.1210/er.2019-00034.

5. Jarvis H., Craig D., Barker R. et al. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of population-based observational studies. PLoS Med. 2020;17(4): e1003100. doi: 10.1371/journal.pmed.1003100

6. Younossi Z., Anstee Q.M., Marietti M. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20. doi: 10.1038/nrgastro.2017.109.

7. Zhao H., Zhang J., Cheng X., Nie X., He B. Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment. J Ovarian Res. 2023;16(1):9. doi: 10.1186/s13048-022-01091-0.

8. Teede H.J., Tay C.T., Laven J.J.E. et al. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023;108(10):2447-2469. doi: 10.1210/clinem/dgad463.

9. Adamyan L.V., Andreeva E.N., Absatarova Yu.S. et al. Clinical guidelines «Polycystic Ovary Syndrome». Problems of Endocrinology. 2022;68(2):112-127. doi: 10.14341/probl12874.

10. Petta S., Ciresi A., Bianco J. et al. Insulin resistance and hyperandrogenism drive steatosis and fibrosis risk in young females with PCOS. PLoS One. 2017;12(11): e0186136. doi: 10.1371/journal.pone.0186136.

11. Bozdag G., Mumusoglu S., Zengin D., Karabulut E., Yildiz B.O. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841-2855. doi: 10.1093/humrep/dew218.

12. Belenkaia L.V., Lazareva L.M., Walker W., Lizneva D.V, Suturina L.V. Criteria, phenotypes and prevalence of polycystic ovary syndrome. Minerva Ginecol. 2019;71(3):211-223. doi: 10.23736/S0026-4784.19.04404-6.

13. Elsayed A.M., Al-Kaabi L.S., Al-Abdulla N.M. et al. Clinical Phenotypes of PCOS: a Cross-Sectional Study. Reprod Sci. 2023;30(11):3261-3272. doi: 10.1007/s43032-023-01262-4.

14. Glueck C.J., Goldenberg N. Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics. Metabolism. 2019;92:108-120. doi: 10.1016/j.metabol.2018.11.002.

15. Barrea L., Muscogiuri G., Pugliese G. et al. Metabolically Healthy Obesity (MHO) vs. Metabolically Unhealthy Obesity (MUO) Phenotypes in PCOS: Association with Endocrine-Metabolic Profile, Adherence to the Mediterranean Diet, and Body Composition. Nutrients. 2021;13(11). doi: 10.3390/nu13113925.

16. Younossi Z.M., Golabi P., de Avila L. et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801. doi: 10.1016/j.jhep.2019.06.021.

17. Targher G., Byrne C.D., Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut. 2020;69(9):1691-1705. doi: 10.1136/gutjnl-2020-320622.

18. Shavkuta G.V., Turkina S.V. NAFLD is a predictor of high risk of development and a co-factor in the progression of cardiovascular diseases. South Russian Journal of Therapeutic Practice. 2024;5(2):29-37. (in Russ.) doi: 10.21886/2712-8156-2024-5-2-29-37.

19. Lazebnik L.B., Turkina S.V. NAFLD Associated Comorbidity. Experimental and Clinical Gastroenterology. 2021;(10):5-13. (in Russ.) doi: 10.31146/1682-8658-ecg-194-10-5-13.

20. Alvarez Y.R., Pico M., Ashokprabhu N. et al. Polycystic Ovarian Syndrome: a Risk Factor for Cardiovascular Disease. Curr Atheroscler Rep. 2023;25(12):1003-1011. doi: 10.1007/s11883-023-01168-1.

21. Rocha A.L.L., Faria L.C., Guimarães T.C.M. et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J Endocrinol Invest. 2017;40(12):1279-1288. doi: 10.1007/s40618-017-0708-9.

22. Singeap A.M., Stanciu C., Huiban L. et al. Association between Nonalcoholic Fatty Liver Disease and Endocrinopathies: Clinical Implications. Can J Gastroenterol Hepatol. 2021;2021:1-8. doi: 10.1155/ 2021/6678142.

23. Spremović Rađenović S,. Pupovac M., Andjić M. et al. Prevalence, Risk Factors, and Pathophysiology of Nonalcoholic Fatty Liver Disease (NAFLD) in Women with Polycystic Ovary Syndrome (PCOS). Biomedicines. 2022;10(1). doi: 10.3390/biomedicines10010131.

24. Shengir M., Chen T., Guadagno E. et al. Non-alcoholic fatty liver disease in premenopausal women with polycystic ovary syndrome: A systematic review and meta-analysis. JGH Open. 2021;5(4):434-445. doi: 10.1002/jgh3.12512.

25. VanWagner L.B., Rinella M.E. Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease. Curr Hepatol Rep. 2016;15(2):75-85. doi: 10.1007/s11901-016-0295-9.

26. Livzan M.A., Syrovenko M.I., Krolevets T.S. Non-alcoholic fatty liver disease and women’s health.Russian Medical Inquiry. 2023;7(5):310-317. (in Russ.) doi: 10.32364/2587-6821-2023-7-5-9

27. Vassilatou E., Vassiliadi D.A., Salambasis K. et al. Increased prevalence of polycystic ovary syndrome in premenopausal women with nonalcoholic fatty liver disease. Eur J Endocrinol. 2015;173(6):739-747. doi: 10.1530/EJE-15-0567.

28. Sarkar M., Terrault N., Chan W. et al. Polycystic ovary syndrome (PCOS) is associated with NASH severity and advanced fibrosis. Liver International. 2020;40(2):355-359. doi: 10.1111/liv.14279.

29. Wu J., Yao X.Y., Shi R.X., Liu S.F., Wang X.Y. A potential link between polycystic ovary syndrome and non-alcoholic fatty liver disease: an update meta-analysis. Reprod Health. 2018;15(1):77. doi: 10.1186/s12978-018-0519-2.

30. Asfari M.M., Sarmini M.T., Baidoun F. et al. Association of non-alcoholic fatty liver disease and polycystic ovarian syndrome. BMJ Open Gastroenterol. 2020;7(1): e000352. doi: 10.1136/bmjgast-2019-000352.

31. Yao K., Zheng H., Peng H. Association between polycystic ovary syndrome and risk of non-alcoholic fatty liver disease: a meta-analysis. Endokrynol Pol. 2023;74(5):520-527. doi: 10.5603/ep.93291.

32. Zhu S., Zhang B., Jiang X. et al. Metabolic disturbances in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Fertil Steril. 2019;111(1):168-177. doi: 10.1016/j.fertnstert.2018.09.013.

33. Li M., Chi X., Wang Y. et al. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther. 2022;7(1):216. doi: 10.1038/s41392-022-01073-0.

34. Cassar S., Misso M.L., Hopkins W.G. et al. Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies. Human Reproduction. 2016;31(11):2619-2631. doi: 10.1093/humrep/dew243.

35. Tosi F., Bonora E., Moghetti P. Insulin resistance in a large cohort of women with polycystic ovary syndrome: a comparison between euglycaemic-hyperinsulinaemic clamp and surrogate indexes. Human Reproduction. 2017;32(12):2515-2521. doi: 10.1093/humrep/dex308.

36. Watt M.J., Miotto P.M., De Nardo W., Montgomery M.K. The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance. Endocr Rev. 2019;40(5):1367-1393. doi: 10.1210/er.2019-00034.

37. Grander C., Grabherr F., Tilg H. Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options. Cardiovasc Res. 2023;119(9):1787-1798. doi: 10.1093/cvr/cvad095.

38. da Silva Rosa S.C., Nayak N., Caymo A.M., Gordon J.W. Mechanisms of muscle insulin resistance and the cross-talk with liver and adipose tissue. Physiol Rep. 2020;8(19): e14607. doi: 10.14814/phy2.14607.

39. Zhao H., Zhang J., Cheng X., Nie X., He B. Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment. J Ovarian Res. 2023;16(1):9. doi: 10.1186/s13048-022-01091-0.

40. Shorakae S., Ranasinha S., Abell S. et al. Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS. Clin Endocrinol (Oxf). 2018;89(5):628-633. doi: 10.1111/cen.13808.

41. Condorelli R.A., Calogero A.E., Di Mauro M. et al. Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index. J Endocrinol Invest. 2018;41(4):383-388. doi: 10.1007/s40618-017-0762-3.

42. Wang D., He B. Current Perspectives on Nonalcoholic Fatty Liver Disease in Women with Polycystic Ovary Syndrome. Diabetes Metab Syndr Obes. 2022;15:1281-1291. doi: 10.2147/DMSO.S362424.

43. Harada M. Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research. Reprod Med Biol. 2022;21(1): e12487. doi: 10.1002/rmb2.12487.

44. McCartney C.R., Campbell R.E. Abnormal GnRH pulsatility in polycystic ovary syndrome: Recent insights. Curr Opin Endocr Metab Res. 2020;12:78-84. doi: 10.1016/j.coemr.2020.04.005.

45. Zhu S., Li Z., Hu C. et al. Imaging-Based Body Fat Distribution in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2021;12:697223. doi: 10.3389/fendo.2021.697223.

46. Cree-Green M., Rahat H., Newcomer B.R. et al. Insulin Resistance, Hyperinsulinemia, and Mitochondria Dysfunction in Nonobese Girls With Polycystic Ovarian Syndrome. J Endocr Soc. 2017;1(7):931-944. doi: 10.1210/js.2017-00192.

47. Kim J.J., Kim D., Yim J.Y. et al. Polycystic ovary syndrome with hyperandrogenism as a risk factor for non-obese non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2017;45(11):1403-1412. doi: 10.1111/apt.14058.

48. Cai J., Wu C.H., Zhang Y. et al. High-free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independent of obesity and insulin resistance.Int J Obes. 2017;41(9):1341-1347. doi: 10.1038/ijo.2017.116.

49. Luci C., Bourinet M., Leclère P.S., Anty R., Gual P. Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies. Front Endocrinol (Lausanne). 2020;11. doi: 10.3389/fendo.2020.597648.

50. Chen Y., Zhao X. The mediating role of insulin resistance in the association between inflammatory score and MAFLD: NHANES 2017-2018. Immun Inflamm Dis. 2024;12(10): e70035. doi: 10.1002/iid3.70035.

51. Bansal S.K., Bansal M.B. Pathogenesis of MASLD and MASH - role of insulin resistance and lipotoxicity. Aliment Pharmacol Ther. 2024;59 Suppl 1: S10-S22. doi: 10.1111/apt.17930.

52. Mladenović D., Vesković M., Šutulović N. et al. Adipose-derived extracellular vesicles - a novel cross-talk mechanism in insulin resistance, non-alcoholic fatty liver disease, and polycystic ovary syndrome. Endocrine. 2024;85(1):18-34. doi: 10.1007/s12020-024-03702-w.

53. Romantsova T.I. Adipose tissue: colors, depots and functions. Obe Metab. 2021;18(3):282-301. doi: 10.14341/omet12748.

54. Abdulkadirova F.R., Ametov A.S., Doskina E.V., Pokrovskaya R.A. The role of the lipotoxicity in the pathogenesis of type 2 diabetes mellitus and obesity. Obe Metab. 2014;11(2):8-12. doi: 10.14341/omet201428-12.

55. Zeng X., Huang Q., Long S., Zhong Q., Mo Z. Mitochondrial Dysfunction in Polycystic Ovary Syndrome. DNA Cell Biol. 2020;39(8):1401-1409. doi: 10.1089/dna.2019.5172.

56. Mansouri A., Gattolliat C.H., Asselah T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology. 2018;155(3):629-647. doi: 10.1053/j.gastro.2018.06.083.

57. Peng K.Y., Watt M.J., Rensen S. et al. Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression. J Lipid Res. 2018;59(10):1977-1986. doi: 10.1194/jlr.M085613.

58. Gonzalez-Franquesa A., Patti M.E. Insulin Resistance and Mitochondrial Dysfunction. In:; 2017:465-520. doi: 10.1007/978-3-319-55330-6_25.

59. Dabravolski S.A., Nikiforov N.G., Eid A.H. et al. Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome.Int J Mol Sci. 2021;22(8):3923. (in Russ.) doi: 10.3390/ijms22083923.

60. Myint M., Oppedisano F., De Giorgi V. et al. Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions. J Transl Med. 2023;21(1):757. doi: 10.1186/s12967-023-04627-0.

61. Chadchan S.B., Singh V., Kommagani R. Female reproductive dysfunctions and the gut microbiota. J Mol Endocrinol. 2022;69(3): R81-R94. doi: 10.1530/JME-21-0238.

62. Sun Y., Gao S., Ye C, Zhao W. Gut microbiota dysbiosis in polycystic ovary syndrome: Mechanisms of progression and clinical applications. Front Cell Infect Microbiol. 2023;13:1142041. doi: 10.3389/fcimb.2023.1142041.

63. Kolodziejczyk A.A., Zheng D., Shibolet O., Elinav E. The role of the microbiome in “NAFLD” and “NASH” EMBO Mol Med. 2019;11(2). doi: 10.15252/emmm.201809302.

64. Mukherjee A.G., Wanjari U.R., Kannampuzha S. et al. The Implication of Mechanistic Approaches and the Role of the Microbiome in Polycystic Ovary Syndrome (PCOS): A Review. Metabolites. 2023;13(1). doi: 10.3390/metabo13010129.

65. Sanchez-Garrido M.A., Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020;35:100937. doi: 10.1016/j.molmet.2020.01.001.

66. Min Q., Geng H., Gao Q., Xu M. The association between gut microbiome and PCOS: evidence from meta-analysis and two-sample mendelian randomization. Front Microbiol. 2023;14:1203902. doi: 10.3389/fmicb.2023.1203902.

67. Safari Z., Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci. 2019;76(8):1541-1558. doi: 10.1007/s00018-019-03011-w.

68. Chen J., Vitetta L. Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications.Int J Mol Sci. 2020;21(15). doi: 10.3390/ijms21155214.

69. Kessoku T., Kobayashi T., Tanaka K. et al. The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target.Int J Mol Sci. 2021;22(15):8161. doi: 10.3390/ijms22158161.


Review

For citations:


Ilovayskaya I.A. Common pathogenetic mechanisms of non-alcoholic fatty liver disease and polycystic ovary syndrome. Experimental and Clinical Gastroenterology. 2024;(10):90-97. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-230-10-90-97

Views: 3


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1682-8658 (Print)