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RFD is the official journal of the International Embryo Transfer Society and the Society for Reproductive Biology.


 

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Low-density lipoprotein receptor affects the fertility of female mice

Tao Guo A B, Liang Zhang B, Dong Cheng C, Tao Liu A B, Liguo An B, Wei-Ping Li A D and Cong Zhang A B D

A Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, China.
B Key Laboratory of Animal Resistance Research, College of Life Science, Shandong Normal University, 88 East Wenhua Road, Ji’nan, Shandong, 250014, China.
C Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Ji’nan, Shandong, 250014, China.
D Corresponding authors. Email: zhangxinyunlife@163.com; liweiping@renji.com

Reproduction, Fertility and Development - http://dx.doi.org/10.1071/RD13436
Submitted: 21 December 2013  Accepted: 7 May 2014   Published online: 15 July 2014


 
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Abstract

Low-density lipoprotein receptor (LDLR) has been demonstrated to play a central role in lipoprotein metabolism, with Ldlr-deficient (Ldlr–/–) mice developing severe dyslipidemia. In the present study we investigated whether Ldlr knockout could harm female reproduction and explored the mechanisms involved. The results indicate that although the number of litters born to Ldlr–/– mice did not differ significantly from that born to controls, the number of pups per litter was significantly lower in the former group. Interestingly, although Ldlr–/– mice were obese, the weight of their ovaries was lower than that in control mice. Serum cholesterol levels was significantly higher in Ldlr–/– mice than in their wild-type counterparts. In contrast, there were significant decreases in cholesterol, triglyceride and total lipid levels in ovaries of Ldlr–/– mice. Both ovarian lipid deposition, as detected by Oil red O staining, and lipid droplets, as evaluated by transmission electron microscopy, supported decreased lipid levels in ovaries from Ldlr–/– mice. In addition, Ldlr–/– mice had fewer ovarian follicles, more atretic follicles, lower oestrogen levels and spent significantly less time in oestrus than did the controls. Superovulation assays indicated immature Ldlr–/– mice ovulated fewer ova than controls. These results indicate that lack of Ldlr results in dyslipidaemia and poor fertility.

Additional keywords: atresia, dyslipidaemia, Ldlr, oestrogen.


References

Argov, N., and Sklan, D. (2004). Expression of mRNA of lipoprotein receptor related protein 8, low density lipoprotein receptor, and very low density lipoprotein receptor in bovine ovarian cells during follicular development and corpus luteum formation and regression. Mol. Reprod. Dev. 68, 169–175.
CrossRef | CAS | PubMed |

Azhar, S., Luo, Y., Medicherla, S., and Reaven, E. (1999). Upregulation of selective cholesteryl ester uptake pathway in mice with deletion of low-density lipoprotein receptor function. J. Cell. Physiol. 180, 190–202.
CrossRef | CAS | PubMed |

Azhar, S., Leers-Sucheta, S., and Reaven, E. (2003). Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and ‘selective’ pathway connection. Front. Biosci. 8, s998.
CrossRef | PubMed |

Basso, F., Freeman, L., Knapper, C. L., Remaley, A., Stonik, J., Neufeld, E. B., Tansey, T., Amar, M. J., Fruchart-Najib, J., and Duverger, N. (2003). Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations. J. Lipid Res. 44, 296–302.
CrossRef | CAS | PubMed |

Boomsma, C. M., Fauser, B. C., and Macklon, N. S. (2008). Pregnancy complications in women with polycystic ovary syndrome. Semin. Reprod. Med. 26, 72–84.
| PubMed |

Britt, K. L., Drummond, A. E., Cox, V. A., Dyson, M., Wreford, N. G., Jones, M. E., Simpson, E. R., and Findlay, J. K. (2000). An age-related ovarian phenotype in mice with targeted disruption of the Cyp 19 (aromatase) gene. Endocrinology 141, 2614–2623.
| CAS | PubMed |

Britt, K. L., Saunders, P. K., McPherson, S. J., Misso, M. L., Simpson, E. R., and Findlay, J. K. (2004a). Estrogen actions on follicle formation and early follicle development. Biol. Reprod. 71, 1712–1723.
CrossRef | CAS | PubMed |

Britt, K. L., Saunders, P. K., McPherson, S. J., Misso, M. L., Simpson, E. R., and Findlay, J. K. (2004b). Estrogen actions on follicle formation and early follicle development. Biol. Reprod. 71, 1712–1723.
CrossRef | CAS | PubMed |

Chun, S.-Y., McGee, E. A., Hsu, S. Y., Minami, S., LaPolt, P. S., Yao, H. H.-C., Bahr, J. M., Gougeon, A., Schomberg, D. W., and Hsueh, A. J. (1999). Restricted expression of WT1 messenger ribonucleic acid in immature ovarian follicles: uniformity in mammalian and avian species and maintenance during reproductive senescence. Biol. Reprod. 60, 365–373.
CrossRef | CAS | PubMed |

Cohen, J. C., Kiss, R. S., Pertsemlidis, A., Marcel, Y. L., McPherson, R., and Hobbs, H. H. (2004). Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872.
CrossRef | CAS | PubMed |

Connelly, M. A., and Williams, D. L. (2004). Scavenger receptor BI: a scavenger receptor with a mission to transport high density lipoprotein lipids. Curr. Opin. Lipidol. 15, 287–295.
CrossRef | CAS | PubMed |

Cui, L. L., Yang, G., Pan, J., and Zhang, C. (2011). Tumor necrosis factor alpha knockout increases fertility of mice. Theriogenology 75, 867–876.
CrossRef | CAS | PubMed |

Dasgupta, S., Sirisha, P., Neelaveni, K., Anuradha, K., Sudhakar, G., and Reddy, B. M. (2012). Role of luteinizing hormone β-subunit gene variants among south Indian women with polycystic ovary syndrome. Gene 494, 51–56.
CrossRef | CAS | PubMed |

Goldstein, J. L., and Brown, M. S. (1985). The LDL receptor and the regulation of cellular cholesterol metabolism. J. Cell Sci. Suppl. 3, 131–137.
CrossRef | CAS | PubMed |

Haghpassand, M., Bourassa, P.-A. K., Francone, O. L., and Aiello, R. J. (2001). Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J. Clin. Invest. 108, 1315–1320.
CrossRef | CAS | PubMed |

Heath, K. E., Gahan, M., Whittall, R. A., and Humphries, S. E. (2001). Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis. Atherosclerosis 154, 243–246.
CrossRef | CAS | PubMed |

Hsu, S. Y., Kubo, M., Chun, S.-Y., Haluska, F. G., Housman, D. E., and Hsueh, A. (1995). Wilms’ tumor protein WT1 as an ovarian transcription factor: decreases in expression during follicle development and repression of inhibin-alpha gene promoter. Mol. Endocrinol. 9, 1356–1366.
| CAS | PubMed |

Hsueh, A. J., Billig, H., and Tsafriri, A. (1994). Ovarian follicle atresia: a hormonally controlled apoptotic process. Endocr. Rev. 15, 707–724.
| CAS | PubMed |

Ishibashi, S., Herz, J., Maeda, N., Goldstein, J. L., and Brown, M. S. (1994). The two-receptor model of lipoprotein clearance: tests of the hypothesis in ‘knockout’ mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc. Natl Acad. Sci. USA 91, 4431–4435.
CrossRef | CAS | PubMed |

Jeon, H., and Blacklow, S. C. (2005). Structure and physiologic function of the low-density lipoprotein receptor. Annu. Rev. Biochem. 74, 535–562.
CrossRef | CAS | PubMed |

Jiménez, L. M., Binelli, M., Bertolin, K., Pelletier, R. M., and Murphy, B. D. (2010). Scavenger receptor-B1 and luteal function in mice. J. Lipid Res. 51, 2362–2371.
CrossRef | PubMed |

Jong, M. C., Willems, V. D. K., Dahlmans, V. E. H., Van Der Boom, H., Kobayashi, K., Oka, K., Siest, G., Chan, L., Hofker, M. H., and Havekes, L. M. (1999). Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor. Biochem. J. 338, 281–287.
CrossRef | CAS | PubMed |

Kreidberg, J. A., Natoli, T. A., McGinnis, L., Donovan, M., Biggers, J. D., and Amstutz, A. (1999). Coordinate action of Wt1 and a modifier gene supports embryonic survival in the oviduct. Mol. Reprod. Dev. 52, 366–375.
CrossRef | CAS | PubMed |

Kwan, B. C., Kronenberg, F., Beddhu, S., and Cheung, A. K. (2007). Lipoprotein metabolism and lipid management in chronic kidney disease. J. Am. Soc. Nephrol. 18, 1246–1261.
CrossRef | CAS | PubMed |

Luo, W., Ito, Y., Mizuta, H., Massaki, K., Hiramatsu, N., Todo, T., Reading, B. J., Sullivan, C. V., and Hara, A. (2013). Molecular cloning and partial characterization of an ovarian receptor with seven ligand binding repeats, an orthologue of low-density lipoprotein receptor, in the cutthroat trout (Oncorhynchus clarki). Comp. Biochem. Physiol. A Mol. Integr. Physiol. 166, 263–271.
CrossRef | CAS | PubMed |

McNatty, K. P., Makris, A., Degrazia, C., Rapin, O., and Ryan, K. J. (1979). The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue, and stromal tissue from human ovaries in vitro. J. Clin. Endocrinol. Metab. 49, 687–699.
CrossRef | CAS | PubMed |

McNatty, K. P., Fidler, A. E., Juengel, J. L., Quirke, L. D., Smith, P. R., Heath, D. A., Lundy, T., O’Connell, A., and Tisdall, D. J. (2000). Growth and paracrine factors regulating follicular formation and cellular function. Mol. Cell. Endocrinol. 163, 11–20.
CrossRef | CAS | PubMed |

Meddings, J. B., and Dietschy, J. M. (1986). Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man. Circulation 74, 805–814.
CrossRef | CAS | PubMed |

Nock, N. L., and Pillai, A. L. C. (2012) Dyslipidemia: genetics and role in the metabolic syndrome. In ‘Dyslipidemia – From Prevention to Treatment.’ (Ed. R. Kelishadi.) pp. 93–126. (InTech: Croatia.)

Oram, J. F., and Lawn, R. M. (2001). ABCA1: the gatekeeper for eliminating excess tissue cholesterol. J. Lipid Res. 42, 1173–1179.
| CAS | PubMed |

Osono, Y., Woollett, L., Herz, J., and Dietschy, J. (1995). Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse. J. Clin. Invest. 95, 1124–1132.
CrossRef | CAS | PubMed |

Phelan, N., O’Connor, A., Kyaw-Tun, T., Correia, N., Boran, G., Roche, H., and Gibney, J. (2010). Lipoprotein subclass patterns in women with polycystic ovary syndrome (PCOS) compared with equally insulin-resistant women without PCOS. J. Clin. Endocrinol. Metab. 95, 3933–3939.
CrossRef | CAS | PubMed |

Repas, T. (2011). Obesity and dyslipidemia. South Dakota Med. 64, 241-3, 245, 247 passim.

Rigotti, A. (2003). The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocr, Rev, 24, 357–387.
CrossRef | CAS |

Robins, E. D., Nelson, L. M., and Hoeg, J. M. (1994). Aberrant hypothalamic–pituitary–ovarian axis in the Watanabe heritable hyperlipidemic rabbit. J. Lipid Res. 35, 52–59.
| CAS | PubMed |

Singh, A., Singh, S., Singh, N., Agrawal, N., and Gopal, K. (2011). Obesity and dyslipidemia. Int. J. Biol. Med. Res. 2, 824–828.

Spady, D. K., Huettinger, M., Bilheimer, D. W., and Dietschy, J. M. (1987). Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit. J. Lipid Res. 28, 32–41.
| CAS | PubMed |

Thung, P., Boot, L., and Mühlbock, O. (1956). Senile changes in the oestrous cycle and in ovarian structure in some inbred strains of mice. Acta Endocrinol. (Copenh.) 23, 8–32.
| PubMed |

Tilly, K. I., Banerjee, S., Banerjee, P. P., and Tilly, J. L. (1995). Expression of the p53 and Wilms’ tumor suppressor genes in the rat ovary: gonadotropin repression in vivo and immunohistochemical localization of nuclear p53 protein to apoptotic granulosa cells of atretic follicles. Endocrinology 136, 1394–1402.
| CAS | PubMed |

Trigatti, B., Rayburn, H., Viñals, M., Braun, A., Miettinen, H., Penman, M., Hertz, M., Schrenzel, M., Amigo, L., and Rigotti, A. (1999). Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc. Natl Acad. Sci. USA 96, 9322–9327.
CrossRef | CAS | PubMed |

Yesilaltay, A., Morales, M. G., Amigo, L., Zanlungo, S., Rigotti, A., Karackattu, S. L., Donahee, M. H., Kozarsky, K. F., and Krieger, M. (2006a). Effects of hepatic expression of the high-density lipoprotein receptor SR-BI on lipoprotein metabolism and female fertility. Endocrinology 147, 1577–1588.
CrossRef | CAS | PubMed |

Yesilaltay, A., Morales, M. G., Amigo, L., Zanlungo, S., Rigotti, A., Karackattu, S. L., Donahee, M. H., Kozarsky, K. F., and Krieger, M. (2006b). Effects of hepatic expression of the high-density lipoprotein receptor SR-BI on lipoprotein metabolism and female fertility. Endocrinology 147, 1577–1588.
CrossRef | CAS | PubMed |

Zhang, T., Dai, P., Cheng, D., Zhang, L., Chen, Z., Meng, X., Zhang, F., Han, X., Liu, J., and Pan, J. (2014). Obesity occurring in apolipoprotein E-knockout mice has mild effects on fertility. Reproduction 147, 141–151.
CrossRef | CAS | PubMed |

Zhou, X., He, W., Huang, Z., Gotto, A. M., Hajjar, D. P., and Han, J. (2008). Genetic deletion of low density lipoprotein receptor impairs sterol-induced mouse macrophage ABCA1 expression. A new SREBP1-dependent mechanism. J. Biol. Chem. 283, 2129–2138.
CrossRef | CAS | PubMed |


   
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