Journal of Food Hygiene and Safety (한국식품위생안전성학회지)

The Korean Society of Food Hygiene and Safety (한국식품위생안전성학회)
권호 표지
DOI QR코드

DOI QR Code

Effects of Dietary Cholesterol on Male Reproductive Tracts by Regulating PCSK9 Gene

콜레스테롤 식이가 Pcsk9 유전자 조절을 통해 남성 생식기관에 미치는 영향

  • Lim, Whasun (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Bae, Hyocheol (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Song, Gwonhwa (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University)
  • 임화선 (고려대학교 생명과학대학 생명공학과) ;
  • 배효철 (고려대학교 생명과학대학 생명공학과) ;
  • 송권화 (고려대학교 생명과학대학 생명공학과)
  • Received : 2016.02.29
  • Accepted : 2016.03.02
  • Published : 2016.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), is a protein mainly secreted by a liver. The PCSK9 plays an important role in low density lipoprotein (LDL) metabolism acting as a repressor of LDL receptor through transportation of the LDLR to the lysosome for degradation. Thus, the PCSK9 inhibitor suppresses PCSK9-regulated degradation of the LDL receptor as a LDL-lowering medicine. However, little is known about the role of PCSK9 in the reproductive system. Therefore, in the present study, we investigated Pcsk9 expression in male reproductive tracts including penises, prostates and testes using rats in response to their diets between a normal diet and a high-fat diet with cholesterol. Based on our previous study, the high-fat diet elevates concentration of total cholesterol and LDL in serum whereas it reduces the concentration of plasma high density lipoprotein (HDL). In addition, it dramatically affects to morphological changes of the male reproductive organs. Consistent with these results, the expression of Pcsk9 was substantially decreased in the penile tissues (P < 0.001) from rats fed a high fat diet as compared to a normal diet. Moreover, it slightly reduced in the prostate and testes (P < 0.05) of rats in response to a high fat diet. Localization of Pcsk9 was predominantly detected in urethral epithelium of penises, cylinder-shaped cells of prostate glands, and spermatogonia, spermatocytes and spermatid of testes of rats. Collectively, results of current study provide invaluable insights into the Pcsk9 gene with respect to its tissue- and cell-specific expression by a high fat diet with cholesterol.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) 유전자는 주로 간에서 분비되며 저밀도지단백질 수용체(LDLR)와 결합체를 이루어 세포 내 저밀도지단백질 수용체를 약화시킴에 따라 저밀도지단백질(LDL) 흡수를 감소시킨다. PCSK9은 심혈관 질환 및 상염색체 우성 가족성 고콜레스테롤혈증과 깊은 연관성을 나타내며 발병 메커니즘을 조절하는 주요한 인자로서 치료제 개발을 위해 많은 연구가 진행 중에 있다. 하지만 생식계통 내에서 PCSK9의 발현 및 기능에 대한 연구가 미비한 현실이다. 이에 본 연구에서는 고 콜레스테롤 식이에 따라 수컷 랫드의 생식기관 (음경, 전립선, 정소) 내 Pcsk9의 발현 변화를 확인하고자 한다. 과도한 콜레스테롤의 축적으로 인한 이상지질혈증은 수컷 랫드의 생식기능장애와 내분비교란을 유발하지만 이를 일으키는 조절 인자와 메커니즘은 명확하게 밝혀지지 않았다. 본 연구진의 선행연구에서는 고 콜레스테롤 식이에 의해 혈중 총 콜레스테롤, 저밀도지단백질 콜레스테롤 레벨이 증가 및 고밀도지단백질(HDL) 콜레스테롤의 감소를 확인하였다. 이 후, Pcsk9의 mRNA 발현은 음경 조직 내에서 80% 감소하는 것으로 나타났고 그 발현은 주로 발기 조직인 음경해면체 및 요도해면체 내 요도상피세포에서 주를 이룸을 확인하였다. 또한 Pcsk9은 고콜레스테롤 식이에 의해 발생하는 전립선 비대증 조직 내에서 20% 감소하는 것으로 나타났다. 그리고 마지막으로 Pcsk9은 고 콜레스테롤 식이를 섭취한 랫드의 정소 조직내에서 정상 정소 조직에 비해 약 28% 감소하였으며 정자발생에 주요한 정세관 내 정원세포, 정모세포, 정세포에서 그 발현이 확인되었다. 본 연구결과를 통해 Pcsk9 유전자가 수컷 랫드 생식기관 (음경, 전립선, 정소)에서 고콜레스테롤 식이에 의해 발현이 감소하는 것을 확인하였으며, 이는 Pcsk9이 남성 생식기관의 성장 및 발달 메커니즘에 중요한 역할을 미칠 것으로 사료된다.

Keywords

References

  1. V, Charlton-Menys., P, N, Durrington.: Human cholesterol metabolism and therapeutic molecules. Experimental physiology, 93, 27-42 (2008). https://doi.org/10.1113/expphysiol.2006.035147
  2. Charlton, M.: Obesity, hyperlipidemia, and metabolic syndrome. Liver transplantation, 15, S83-89 (2009). https://doi.org/10.1002/lt.21914
  3. Jones, P. J.: Dietary cholesterol and the risk of cardiovascular disease in patients: a review of the Harvard Egg Study and other data. International journal of clinical practice, 63, 1-8 (2009).
  4. McNamara, D. J.: Dietary cholesterol and atherosclerosis. Biochimica et biophysica acta, 1529, 310-320 (2000). https://doi.org/10.1016/S1388-1981(00)00156-6
  5. Puglielli, L., Tanzi, R. E. and Kovacs, D. M.: Alzheimer's disease: the cholesterol connection. Nature neuroscience, 6, 345-351 (2003). https://doi.org/10.1038/nn0403-345
  6. Hu, J., La, Vecchia, C., de, Groh, M., Negri, E., Morrison, H., Mery, L.: Dietary cholesterol intake and cancer. Annals of oncology, 23, 491-500 (2012). https://doi.org/10.1093/annonc/mdr155
  7. Gupta R, S., Dixit V, P.: Effect of dietary cholesterol on spermatogenesis. Zeitschrift fur Ernahrungswissenschaft, 27, 236-243 (1988). https://doi.org/10.1007/BF02019512
  8. Lim W., Bae H., Sohn J.Y., Jeong W., Kim S.H., Song G.: Dietary cholesterol affects expression of prostatic acid phosphatase in reproductive organs of male rats. Biochemical and biophysical research communications, 456, 421-427, (2015). https://doi.org/10.1016/j.bbrc.2014.11.100
  9. Miner, M., Billups, K, L.: Erectile dysfunction and dyslipidemia: relevance and role of phosphodiesterase type-5 inhibitors and statins. The journal of sexual medicine, 5, 1066-1078 (2008).
  10. Zhang, D, W., Garuti, R., Tang, W, J., Cohen, J, C., Hobbs, H, H.: Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc Natl Acad Sci U S A, 105, 13045-13050 (2008). https://doi.org/10.1073/pnas.0806312105
  11. Brown, M, S., Goldstein, J, L.: The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell, 89, 331-340 (1997). https://doi.org/10.1016/S0092-8674(00)80213-5
  12. Abifadel, M., Varret, M., Rabès, JP., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derré, A., Villéger, L., Farnier, M., Beucler, I., Bruckert, E., Chambaz, J., Chanu, B., Lecerf, JM., Luc, G., Moulin, P., Weissenbach, J., Prat, A., Krempf, M., Junien, C., Seidah, NG., Boileau, C.: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature genetics, 34, 154-156 (2003). https://doi.org/10.1038/ng1161
  13. Kim S.C.: Hyperlipidemia and erectile dysfunction. Asian journal of andrology, 2, 161-166 (2000).
  14. Musicki, B., Liu, T., Lagoda, G,A., Strong, T,D., Sezen, S,F., Johnson, J,M., Burnett, A,L.: Hypercholesterolemia-induced erectile dysfunction: endothelial nitric oxide synthase (eNOS) uncoupling in the mouse penis by NAD(P)H oxidase. The journal of sexual medicine, 7, 3023-3032 (2010). https://doi.org/10.1111/j.1743-6109.2010.01880.x
  15. Kim J.H., Klyachkin, M,L., Svendsen, E., Davies, M,G., Hagen, P,O., Carson, C,C.: Experimental hypercholesterolemia in rabbits induces cavernosal atherosclerosis with endothelial and smooth muscle cell dysfunction. The Journal of urology, 151, 198-205 (1994). https://doi.org/10.1016/S0022-5347(17)34916-9
  16. Ahn J., Lim U., Weinstein, S,J., Schatzkin, A., Hayes, R,B., Virtamo, J., Albanes, D.: Prediagnostic total and high-density lipoprotein cholesterol and risk of cancer. Cancer epidemiology, biomarkers & prevention, 18, 2814-2821 (2009). https://doi.org/10.1158/1055-9965.EPI-08-1248
  17. Mondul, A, M., Clipp, S, L., Helzlsouer, K, J., Platz, E, A.: Association between plasma total cholesterol concentration and incident prostate cancer in the CLUE II cohort. Cancer Cause Control, 21, 61-68 (2010). https://doi.org/10.1007/s10552-009-9434-8
  18. Zhuang, L., Kim, J., Adam, R, M., Solomon, K, R., Freeman, M, R.: Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. The Journal of clinical investigation, 115, 959-968 (2005). https://doi.org/10.1172/JCI200519935
  19. Freeman, M, R., Solomon, K, R.: Cholesterol and benign prostate disease. Differentiation, 82, 244-252 (2011). https://doi.org/10.1016/j.diff.2011.04.005
  20. Martinez-Martos, JM., Arrazola, M., Mayas, M,D., Carrera-Gonzalez, M,P., Garcia, M,J., Ramírez-Exposito, M,J.: Dietinduced hypercholesterolemia impaired testicular steroidogenesis in mice through the renin-angiotensin system. Gen Comp Endocrinol, 173, 15-19 (2011). https://doi.org/10.1016/j.ygcen.2011.04.015
  21. Diaz-Fontdevila, M., Bustos-Obregon, E.: Cholesterol and polyunsaturated acid enriched diet: effect on kinetics of the acrosome reaction in rabbit spermatozoa. Molecular reproduction and development, 35, 176-180 (1993). https://doi.org/10.1002/mrd.1080350211