Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Abnormal expression of uncoupling protein-2 correlates with CYP11A1 expression in polycystic ovary syndrome

Yun Liu A , Hong Jiang B , Ling-Yun He A , Wu-Jian Huang A , Xiao-Yu He A and Fu-Qi Xing C D
+ Author Affiliations
- Author Affiliations

A Center for Reproductive Medicine, Fuzhou General Hospital, No. 156 Xi’erhuan North Road, Fuzhou 350025, Fujian Province, China.

B Department of Vasculocardiology, Fuzhou General Hospital, No. 156 Xi’erhuan North Road, Fuzhou 350025, Fujian Province, China.

C Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University, Tonghe Road 1838, Guangzhou 510515, Guangdong Province, China.

D Corresponding author. Email: liuyun95@yahoo.com.cn

Reproduction, Fertility and Development 23(4) 520-526 https://doi.org/10.1071/RD10266
Submitted: 18 October 2010  Accepted: 2 November 2010   Published: 11 April 2011

Abstract

Polycystic ovary syndrome (PCOS) may result from hypersensitivity to insulin, which is negatively regulated by uncoupling protein (UCP)-2. Because cholesterol side-chain cleavage enzyme (CYP11A1) is closely linked to PCOS, the expression of UCP-2 and CYP11A1 in ovarian tissues from PCOS patients was examined in the present study. Twelve PCOS patients with hyperandrogenaemia who underwent laparoscopic ovarian wedge resection and 12 age-matched control patients who underwent contralateral ovarian biopsy were enrolled in the study. UCP-2 expression in early stage (primordial, primary and secondary) and late stage (sinus and mature) follicles was examined using immunohistochemistry, whereas UCP-2 and CYP11A1 mRNA and protein levels in ovarian tissue were determined using quantitative reverse transcription–polymerase chain reaction and western blot analyses, respectively. UCP-2 expression increased significantly with follicular development in both control and PCOS tissue, with expression in early stage follicles from PCOS patients significantly greater than that in controls. In addition, both UCP-2 and CYP11A1mRNA and protein levels, mean fasting blood glucose concentrations and fasting serum insulin levels were significantly higher in PCOS patients compared with the control group. Finally, a significant correlation between UCP-2 and CYP11A1 expression was found in PCOS but not control patients. In conclusion, in PCOS patients, there was a correlation between UCP-2 and CYP11A1 expression, which was significantly higher than in the control group. These changes in UCP-2 and CYP11A1 expression may mediate follicle development in PCOS.

Additional keywords: cholesterol side-chain cleavage enzyme, hyperandrogenism, insulin resistance.


References

Astrup, A., Toubro, S., Dalgaard, L. T., Urhammer, S. A., Sorensen, T. I., and Pedersen, O. (1999). Impact of the v/v 55 polymorphism of the uncoupling protein 2 gene on 24-h energy expenditure and substrate oxidation. Int. J. Obes. Relat. Metab. Disord. 23, 1030–1034.
Impact of the v/v 55 polymorphism of the uncoupling protein 2 gene on 24-h energy expenditure and substrate oxidation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXnt1Ckurs%3D&md5=b222b3547a11fec40c09456e8b9079e4CAS | 10557023PubMed |

Chan, C. B., MacDonald, P. E., Saleh, M. C., Johns, D. C., Marbàn, E., and Wheeler, M. B. (1999). Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets. Diabetes 48, 1482–1486.
Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXktFanu74%3D&md5=309fb7596054f68d4a5f356fa902545dCAS | 10389858PubMed |

Chan, C. B., De Leo, D., Joseph, J. W., McQuaid, T. S., Ha, X. F., Xu, F., Tsushima, R. G., Pennefather, P. S., Salapatek, A. M., and Wheeler, M. B. (2001). Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 50, 1302–1310.
Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXkvFSgsLY%3D&md5=bcea5ca2a59a81ca2a79c6cfb64058adCAS | 11375330PubMed |

Daneshmand, S., Weitsman, S. R., Navab, A., Jakimiuk, A. J., and Magoffin, D. A. (2002). Overexpression of theca-cell messenger RNA in polycystic ovary syndrome does not correlate with polymorphisms in the cholesterol side-chain cleavage and 17-hydroxylase/C17–20 lyase promoters. Fertil. Steril. 77, 274–280.
Overexpression of theca-cell messenger RNA in polycystic ovary syndrome does not correlate with polymorphisms in the cholesterol side-chain cleavage and 17-hydroxylase/C17–20 lyase promoters.Crossref | GoogleScholarGoogle Scholar | 11821083PubMed |

Diamanti-Kandarakis, E., Bartzis, M. I., Bergiele, A. T., Tsianateli, T. C., and Kouli, C. R. (2000). Microsatellite polymorphism (tttta) (n) at –528 base pairs of gene cyp11alpha influences hyperandrogenemia in patients with polycystic ovary syndrome. Fertil. Steril. 73, 735–741.
Microsatellite polymorphism (tttta) (n) at –528 base pairs of gene cyp11alpha influences hyperandrogenemia in patients with polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3c7pvVWjsw%3D%3D&md5=bac3191b3499d17d511f67c5a54d4246CAS | 10731534PubMed |

Gaasenbeek, M., Powell, B. L., Sovio, U., Haddad, L., Gharani, N., Bennett, A., Groves, C. J., Rush, K., Goh, M. J., Conway, G. S., Ruokonen, A., Martikainen, H., Pouta, A., Taponen, S., Hartikainen, A. L., Halford, S., Järvelin, M. R., Franks, S., and McCarthy, M. I. (2004). Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. J. Clin. Endocrinol. Metab. 89, 2408–2413.
Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXjvFyrur0%3D&md5=88461181292f00d6a517f7114846f7c1CAS | 15126571PubMed |

Gharani, N., Waterworth, D. M., Batty, S., White, D., Gilling-Smith, C., Conway, G. S., McCarthy, M., Franks, S., and Williamson, R. (1997). Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum. Mol. Genet. 6, 397–402.
Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXhvFKlsbc%3D&md5=1448e130aecb115059358830389a2d7bCAS | 9147642PubMed |

Jerome, S., and Robert, B. (2004). ‘Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management.’ (Elsevier Saunders: Philadephia.)

Joseph, J. W., Koshkin, V., Zhang, C. Y., Wang, J., Lowell, B. B., Chan, C. B., and Wheeler, M. B. (2002). Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51, 3211–3219.
Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xos1ahtLw%3D&md5=b708962d90191285af21870a3cd52894CAS | 12401712PubMed |

Krauss, S., Zhang, C. Y., and Lowell, B. B. (2002). A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2. Proc. Natl Acad. Sci. USA 99, 118–122.
A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xlt1Chtw%3D%3D&md5=4c57a80cb2534e23be07ad09803de9cbCAS |

Legro, R. S., and Strauss, J. F. (2002). Molecular progress in infertility: polycystic ovary syndrome. Fertil. Steril. 78, 569–576.
Molecular progress in infertility: polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 12215335PubMed |

Miller, W. L. (2002). Androgen biosynthesis from cholesterol to DHEA. Mol. Cell. Endocrinol. 198, 7–14.
Androgen biosynthesis from cholesterol to DHEA.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXovFCguw%3D%3D&md5=de8111c310022ce6d949e476403860afCAS | 12573809PubMed |

Nestler, J. E., Jakubowicz, D. J., de Vargas, A. F., Brik, C., Quintero, N., and Medina, F. (1998). Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositol glycan mediators as the signal transduction system. J. Clin. Endocrinol. Metab. 83, 2001–2005.
Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositol glycan mediators as the signal transduction system.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXjslCgurs%3D&md5=dc86b551d2869ccaf8240b2440617d20CAS | 9626131PubMed |

Patel, K., Coffler, M. S., Dahan, M. H., Malcom, P. J., Deutsch, R., and Chang, R. J. (2004). Relationship of GnRH stimulated LH release to episodic LH secretion and baseline endocrine–metabolic measures in women with polycystic ovary syndrome. Clin. Endocrinol. 60, 67–74.
Relationship of GnRH stimulated LH release to episodic LH secretion and baseline endocrine–metabolic measures in women with polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhslGmtLo%3D&md5=879c0f19eb1a304c8db4545fcd003dacCAS |

Pedraza, N., Solanes, G., Iglesias, R., Vázquez, M., Giralt, M., and Villarroya, F. (2001). Differential regulation of expression of genes encoding uncoupling proteins 2 and 3 in brown adipose tissue during lactation in mice. Biochem. J. 355, 105–111.
Differential regulation of expression of genes encoding uncoupling proteins 2 and 3 in brown adipose tissue during lactation in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXjtVOktbs%3D&md5=9519fcf7a2ca186c3ba6641012703420CAS | 11256954PubMed |

Pusalkar, M., Meherji, P., Gokral, J., Chinnaraj, S., and Maitra, A. (2009). CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome. Fertil. Steril. 92, 653–659.
CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXht1GntbrO&md5=6550bf3359adf50c727b4cbf4c333ad0CAS | 18725155PubMed |

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2004). Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. l9, 41–47.

San Millán, J. L., Sancho, J., Calvo, R. M., and Escobar-Morreale, H. F. (2001). Role of the pentanucleotide (tttta) (n) polymorphism in the promoter of the cyp11a gene in the pathogenesis of hirsutism. Fertil. Steril. 75, 797–802.
Role of the pentanucleotide (tttta) (n) polymorphism in the promoter of the cyp11a gene in the pathogenesis of hirsutism.Crossref | GoogleScholarGoogle Scholar | 11287037PubMed |

Stuart, J. A., Cadenas, S., Jekabsons, M. B., Roussel, D., and Brand, M. D. (2001). Mitochondrial proton leak and the uncoupling protein 1 homologues. Biochim. Biophys. Acta 1504, 144–158.
Mitochondrial proton leak and the uncoupling protein 1 homologues.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXhsFSitLw%3D&md5=88df0ee87875d6169f1658d5b1a7f522CAS | 11239491PubMed |

Jean, P. B., and John, E. N. (2006). Commentary: Polycystic ovary syndrome: a syndrome of ovarian hypersensitivity to insulin? Clin. Endocrinol. Metab. 91, 22–24.
Commentary: Polycystic ovary syndrome: a syndrome of ovarian hypersensitivity to insulin?Crossref | GoogleScholarGoogle Scholar |

Zhang, C. Y., Baffy, G., Perret, P., Krauss, S., Peroni, O., Grujic, D., Hagen, T., Vidal-Puig, A. J., Boss, O., Kim, Y. B., Zheng, X. X., Wheeler, M. B., Shulman, G. I., Chan, C. B., and Lowell, B. B. (2001). Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and Type 2 diabetes. Cell 105, 745–755.
Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and Type 2 diabetes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXltVSlsbc%3D&md5=c2d25670d588c84b6c57f8385ba686d0CAS | 11440717PubMed |