Hostname: page-component-76d6cb85b7-92wsb Total loading time: 0 Render date: 2026-07-14T00:55:05.800Z Has data issue: false hasContentIssue false
  • English
  • Français

Obeticholic acid treatment of mice to promote fertilization and reproduction

Published online by Cambridge University Press:  01 September 2023

Ming Liang ,
Huailiang Yang ,
Lanyong Xu  and
Longqiao Cao Open the ORCID record for Longqiao Cao [Opens in a new window]
Ming Liang
Affiliation:
Department of Reproductive Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, Shandong Province, China
Huailiang Yang
Affiliation:
Department of Reproductive Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, Shandong Province, China
Lanyong Xu
Affiliation:
The People’s Hospital of Gaotang, Gaotang People’s Hospital Affiliated to Jining Medical College, Gaotang, 252800, Shandong Province, China
Longqiao Cao*
Affiliation:
Department of Reproductive Medicine, The First People’s Hospital of Jining, Jining, 272011, Shandong Province, China
*
Corresponding author: Longqiao Cao; Email: caolongqiang2023@163.com
Get access Rights & Permissions [Opens in a new window]

Summary

Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, has been demonstrated to ameliorate the histopathological characteristics of liver damage. Nonetheless, the systemic safety profile of OCA with regard to reproduction and development remains poorly understood. In the present study, we conducted a dose–response experiment by administering OCA at doses of 5 mg/kg, 10 mg/kg, or 20 mg/kg through tube feeding to investigate its effect on reproductive development and fertilization rate in both male and female mice. Furthermore, we evaluated the levels of protein and mitochondrial function in the placenta through western blot, qPCR, and scanning electron microscopy. The results showed that 10 mg/kg and 20 mg/kg OCA doses significantly reduced the rate of placental implantation (P < 0.05). Also, OCA increased maternal body weight. In addition, OCA increased levels of FXR and TGR5 and produced changes in oxidative stress levels (P < 0.05). Mitochondrial activity result found that 10 mg/kg and 20 mg/kg of OCA significantly reduced the mitophagy autosomes/nucleus compared with the normal control group (P < 0.05). What is more, there was no significant difference in sperm count after OCA intervention in either C57BL/10 mice or BALB/c mice. Overall, we demonstrated that OCA treatment protected against placental implantation by suppressing placental oxidative stress and mitochondrial activity.

Keywords

Mitochondrial activityObeticholic acidOxidative stressReproduction

Information

Type
Research Article
Information
Zygote , Volume 31 , Issue 6 , December 2023 , pp. 527 - 536
Check for updates
Copyright
© The Author(s), 2023. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Abenavoli, L., Falalyeyeva, T., Boccuto, L., Tsyryuk, O. and Kobyliak, N. (2018). Obeticholic acid: A new era in the treatment of nonalcoholic fatty liver disease. Pharmaceuticals, 11(4). doi: 10.3390/ph11040104 CrossRefGoogle ScholarPubMed
Adkins-Regan, E. (2015). Hit or miss: Fertilization outcomes of natural inseminations by Japanese quail. PLOS ONE, 10(7), e0131786. doi: 10.1371/journal.pone.0131786 CrossRefGoogle ScholarPubMed
Ali, A. H., Carey, E. J. and Lindor, K. D. (2015). Recent advances in the development of farnesoid X receptor agonists. Annals of Translational Medicine, 3(1), 5. doi: 10.3978/j.issn.2305-5839.2014.12.06 Google ScholarPubMed
Andrews, P. A., Blanset, D., Costa, P. L., Green, M., Green, M. L., Jacobs, A., Kadaba, R., Lebron, J. A., Mattson, B., McNerney, M. E., Minck, D., Oliveira, L. C., Theunissen, P. T. and DeGeorge, J. J. (2019). Analysis of exposure margins in developmental toxicity studies for detection of human teratogens. Regulatory Toxicology and Pharmacology, 105, 62–68. doi: 10.1016/j.yrtph.2019.04.005 CrossRefGoogle ScholarPubMed
Baghdasaryan, A., Claudel, T., Gumhold, J., Silbert, D., Adorini, L., Roda, A., Vecchiotti, S., Gonzalez, F. J., Schoonjans, K., Strazzabosco, M., Fickert, P. and Trauner, M. (2011). Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO3 output. Hepatology, 54(4), 1303–1312. doi: 10.1002/hep.24537 CrossRefGoogle Scholar
Boland, M. L., Laker, R. C., Mather, K., Nawrocki, A., Oldham, S., Boland, B. B., Lewis, H., Conway, J., Naylor, J., Guionaud, S., Feigh, M., Veidal, S. S., Lantier, L., McGuinness, O. P., Grimsby, J., Rondinone, C. M., Jermutus, L., Larsen, M. R., Trevaskis, J. L. and Rhodes, C. J. (2020). Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nature Metabolism, 2(5), 413–431. doi: 10.1038/s42255-020-0209-6 CrossRefGoogle ScholarPubMed
Borg, C. L., Wolski, K. M., Gibbs, G. M. and O’Bryan, M. K. (2010). Phenotyping male infertility in the mouse: How to get the most out of a “non-performer”. Human Reproduction Update, 16(2), 205–224. doi: 10.1093/humupd/dmp032 CrossRefGoogle ScholarPubMed
Borrelli, A., Bonelli, P., Tuccillo, F. M., Goldfine, I. D., Evans, J. L., Buonaguro, F. M. and Mancini, A. (2018). Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. Redox Biology, 15, 467–479. doi: 10.1016/j.redox.2018.01.009 CrossRefGoogle ScholarPubMed
Burkholder, T., Foltz, C., Karlsson, E., Linton, C. G. and Smith, J. M. (2012). Health evaluation of experimental laboratory mice. Current Protocols in Mouse Biology, 2, 145–165. doi: 10.1002/9780470942390.mo110217 CrossRefGoogle ScholarPubMed
Chen, Y. H., Hu, X. G., Zhou, Y., Yu, Z., Fu, L., Zhang, G. B., Bo, Q. L., Wang, H., Zhang, C. and Xu, D. X. (2016). Obeticholic acid protects against lipopolysaccharide-induced fetal death and intrauterine growth restriction through its anti-inflammatory activity. Journal of Immunology, 197(12), 4762–4770. doi: 10.4049/jimmunol.1601331 CrossRefGoogle ScholarPubMed
Chen, W., Gao, X. X., Ma, L., Liu, Z. B., Li, L., Wang, H., Gao, L., Xu, D. X. and Chen, Y. H. (2019). Obeticholic acid protects against gestational cholestasis-induced fetal intrauterine growth restriction in mice. Oxidative Medicine and Cellular Longevity, 2019, 7419249. doi: 10.1155/2019/7419249 CrossRefGoogle ScholarPubMed
De Angioletti, M., Rovira, A., Notaro, R., Camacho Vanegas, O., Sadelain, M. and Luzzatto, L. (2001). Glucose 6-phosphate dehydrogenase expression is less prone to variegation when driven by its own promoter. Gene, 267(2), 221–231. doi: 10.1016/s0378-1119(01)00394-8 CrossRefGoogle ScholarPubMed
Erice, O., Labiano, I., Arbelaiz, A., Santos-Laso, A., Munoz-Garrido, P., Jimenez-Agüero, R., Olaizola, P., Caro-Maldonado, A., Martín-Martín, N., Carracedo, A., Lozano, E., Marin, J. J., O’Rourke, C. J., Andersen, J. B., Llop, J., Gómez-Vallejo, V., Padro, D., Martin, A., Marzioni, M.,... Banales, J. M. (2018). Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. Biochimica et Biophysica Acta. Molecular Basis of Disease, 1864(4 Pt B), 1335–1344. doi: 10.1016/j.bbadis.2017.08.016 CrossRefGoogle ScholarPubMed
Falk, M. C., Zheng, X., Chen, D., Jiang, Y., Liu, Z. and Lewis, K. D. (2017). Developmental and reproductive toxicological evaluation of arachidonic acid (ARA)-Rich oil and docosahexaenoic acid (DHA)-Rich oil. Food and Chemical Toxicology, 103, 270–278. doi: 10.1016/j.fct.2017.03.011 CrossRefGoogle ScholarPubMed
Gai, Z., Krajnc, E., Samodelov, S. L., Visentin, M. and Kullak-Ublick, G. A. (2020). Obeticholic acid ameliorates valproic acid-induced hepatic steatosis and oxidative stress. Molecular Pharmacology, 97(5), 314–323. doi: 10.1124/mol.119.118646 CrossRefGoogle ScholarPubMed
García-Vázquez, F. A., Gadea, J., Matás, C. and Holt, W. V. (2016). Importance of sperm morphology during sperm transport and fertilization in mammals. Asian Journal of Andrology, 18(6), 844–850. doi: 10.4103/1008-682X.186880 CrossRefGoogle ScholarPubMed
Griffith, O. W. (1980). Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Analytical Biochemistry, 106(1), 207–212. doi: 10.1016/0003-2697(80)90139-6 CrossRefGoogle ScholarPubMed
Gulamhusein, A. F. and Hirschfield, G. M. (2020). Primary biliary cholangitis: Pathogenesis and therapeutic opportunities. Nature Reviews. Gastroenterology and Hepatology, 17(2), 93–110. doi: 10.1038/s41575-019-0226-7 CrossRefGoogle ScholarPubMed
Haczeyni, F., Poekes, L., Wang, H., Mridha, A. R., Barn, V., Geoffrey Haigh, W., Ioannou, G. N., Yeh, M. M., Leclercq, I. A., Teoh, N. C. and Farrell, G. C. (2017). Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice. Obesity, 25(1), 155–165. doi: 10.1002/oby.21701 CrossRefGoogle Scholar
Hirschfield, G. M., Dyson, J. K., Alexander, G. J. M., Chapman, M. H., Collier, J., Hübscher, S., Patanwala, I., Pereira, S. P., Thain, C., Thorburn, D., Tiniakos, D., Walmsley, M., Webster, G. and Jones, D. E. J. (2018). The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut, 67(9), 1568–1594. doi: 10.1136/gutjnl-2017-315259 CrossRefGoogle ScholarPubMed
Huang, S., Wu, Y., Zhao, Z., Wu, B., Sun, K., Wang, H., Qin, L., Bai, F., Leng, Y. and Tang, W. (2021) A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage. Metabolism: Clinical and Experimental, 120, 154797. doi: 10.1016/j.metabol.2021.154797 CrossRefGoogle ScholarPubMed
Husted, S., Minutello, F., Pinna, A., Tougaard, S. L., Møs, P. and Kopittke, P. M. (2023). What is missing to advance foliar fertilization using nanotechnology? Trends in Plant Science, 28(1), 90–105. doi: 10.1016/j.tplants.2022.08.017 CrossRefGoogle ScholarPubMed
Javitt, N. B. (2021). Obeticholic acid and hepatic bile acids: Excellent study faulty conclusion. Journal of Hepatology, 74(5), 1267. doi: 10.1016/j.jhep.2021.01.031 CrossRefGoogle ScholarPubMed
Jiang, H. B., Zhang, K. Q., Zou, H. T., Ma, Y. J., Qu, Q. B., Gu, Y. R. and Shen, S. Z. (2021). [Effects of different fertilization patterns on nitrogen leaching loss from paddy fields under reduced nitrogen]. Huan Jing Ke Xue, 42(11), 5405–5413. doi: 10.13227/j.hjkx.202104111 Google ScholarPubMed
Kanteraki, A. E., Isari, E. A., Svarnas, P. and Kalavrouziotis, I. K. (2022). Biosolids: The Trojan horse or the beautiful Helen for soil fertilization? Science of the Total Environment, 839, 156270. doi: 10.1016/j.scitotenv.2022.156270 CrossRefGoogle ScholarPubMed
Lee, K. C., Wu, P. S. and Lin, H. C. (2023). Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis. Clinical and Molecular Hepatology, 29(1), 77–98. doi: 10.3350/cmh.2022.0237 CrossRefGoogle ScholarPubMed
Markham, A. and Keam, S. J. (2016). Obeticholic acid: First global approval. Drugs, 76(12), 1221–1226. doi: 10.1007/s40265-016-0616-x CrossRefGoogle ScholarPubMed
Mayo, M. J. (2022). Mechanisms and molecules: What are the treatment targets for primary biliary cholangitis? Hepatology, 76(2), 518–531. doi: 10.1002/hep.32405 CrossRefGoogle ScholarPubMed
Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., Kowdley, K. V., McCullough, A., Terrault, N., Clark, J. M., Tonascia, J., Brunt, E. M., Kleiner, D. E., Doo, E. and NASH Clinical Research Network. (2015). Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (flint): A multicentre, randomised, placebo-controlled trial. Lancet, 385(9972), 956–965. doi: 10.1016/S0140-6736(14)61933-4 CrossRefGoogle Scholar
Nevens, F., Andreone, P., Mazzella, G., Strasser, S. I., Bowlus, C., Invernizzi, P., Drenth, J. P., Pockros, P. J., Regula, J., Beuers, U., Trauner, M., Jones, D. E., Floreani, A., Hohenester, S., Luketic, V., Shiffman, M., van Erpecum, K. J., Vargas, V. and Vincent, C. (2016). A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. New England Journal of Medicine, 375(7), 631–643. doi: 10.1056/NEJMoa1509840 CrossRefGoogle ScholarPubMed
Niringiyumukiza, J. D., Cai, H. and Xiang, W. (2018). Prostaglandin E2 involvement in mammalian female fertility: Ovulation, fertilization, embryo development and early implantation. Reproductive Biology and Endocrinology: RB&E, 16(1), 43. doi: 10.1186/s12958-018-0359-5 CrossRefGoogle ScholarPubMed
Ohkawa, H., Ohishi, N. and Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351–358. doi: 10.1016/0003-2697(79)90738-3 CrossRefGoogle ScholarPubMed
Pataia, V., McIlvride, S., Papacleovoulou, G., Ovadia, C., McDonald, J. A. K., Wahlström, A., Jansen, E., Adorini, L., Shapiro, D., Marchesi, J. R., Marschall, H. U. and Williamson, C. (2020). Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia. American Journal of Physiology. Gastrointestinal and Liver Physiology, 319(2), G197–G211. doi: 10.1152/ajpgi.00126.2020 CrossRefGoogle Scholar
Pitnick, S., Wolfner, M. F. and Dorus, S. (2020). Post-ejaculatory modifications to sperm (PEMS). Biological Reviews of the Cambridge Philosophical Society, 95(2), 365–392. doi: 10.1111/brv.12569 CrossRefGoogle ScholarPubMed
Polyzos, S. A., Kountouras, J. and Mantzoros, C. S. (2020). Obeticholic acid for the treatment of nonalcoholic steatohepatitis: Expectations and concerns. Metabolism: Clinical and Experimental, 104, 154144. doi: 10.1016/j.metabol.2020.154144 CrossRefGoogle ScholarPubMed
Töpfer-Petersen, E., Petrounkina, A. M. and Ekhlasi-Hundrieser, M. (2000). Oocyte-sperm interactions. Animal Reproduction Science, 60–61, 653–662. doi: 10.1016/s0378-4320(00)00128-7 CrossRefGoogle ScholarPubMed
Tsai, Y. L., Liu, C. W., Hsu, C. F., Huang, C. C., Lin, M. W., Huang, S. F., Li, T. H., Lee, K. C., Hsieh, Y. C., Yang, Y. Y., Lee, T. Y., Liu, H. M., Huang, Y. H., Hou, M. C. and Lin, H. C. (2020). Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway. Clinical Science, 134(15), 2055–2073. doi: 10.1042/CS20200452 CrossRefGoogle ScholarPubMed
Verbeke, L., Mannaerts, I., Schierwagen, R., Govaere, O., Klein, S., Vander Elst, I., Windmolders, P., Farre, R., Wenes, M., Mazzone, M., Nevens, F., van Grunsven, L. A., Trebicka, J. and Laleman, W. (2016). FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Scientific Reports, 6, 33453. doi: 10.1038/srep33453 CrossRefGoogle Scholar
Wang, C., Ma, H., Feng, Z., Yan, Z., Song, B., Wang, J., Zheng, Y., Hao, W., Zhang, W., Yao, M. and Wang, Y. (2022). Integrated organic and inorganic fertilization and reduced irrigation altered prokaryotic microbial community and diversity in different compartments of wheat root zone contributing to improved nitrogen uptake and wheat yield. Science of the Total Environment, 842, 156952. doi: 10.1016/j.scitotenv.2022.156952 CrossRefGoogle ScholarPubMed
Wu, H., Liu, G., He, Y., Da, J. and Xie, B. (2019). Obeticholic acid protects against diabetic cardiomyopathy by activation of FXR/Nrf2 signaling in db/db mice. European Journal of Pharmacology, 858, 172393. doi: 10.1016/j.ejphar.2019.05.022 CrossRefGoogle ScholarPubMed
Wu, L., Han, Y., Zheng, Z., Zhu, S., Chen, J., Yao, Y., Yue, S., Teufel, A., Weng, H., Li, L. and Wang, B. (2021). Obeticholic acid inhibits anxiety via alleviating gut microbiota-mediated microglia accumulation in the brain of high-fat high-sugar diet mice. Nutrients, 13(3). doi: 10.3390/nu13030940 CrossRefGoogle ScholarPubMed
Xiong, X., Ren, Y., Cui, Y., Li, R., Wang, C. and Zhang, Y. (2017). Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation. Biomedicine and Pharmacotherapy, 96, 1292–1298. doi: 10.1016/j.biopha.2017.11.083 CrossRefGoogle ScholarPubMed
Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J. and Boursier, J. (2019). Obeticholic acid for the treatment of non-alcoholic steatohepatitis: Interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet, 394(10215), 2184–2196. doi: 10.1016/S0140-6736(19)33041-7 CrossRefGoogle ScholarPubMed
Zhang, C., Gan, Y., Lv, J. W., Qin, M. Q., Hu, W. R., Liu, Z. B., Ma, L., Song, B. D., Li, J., Jiang, W. Y., Wang, J. Q., Wang, H. and Xu, D. X. (2020). The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice. International Immunopharmacology, 83, 106442. doi: 10.1016/j.intimp.2020.106442 CrossRefGoogle ScholarPubMed
Zhang, X., Xiao, G., Bol, R., Wang, L., Zhuge, Y., Wu, W., Li, H. and Meng, F. (2021). Influences of irrigation and fertilization on soil N cycle and losses from wheat-maize cropping system in northern China. Environmental Pollution, 278, 116852. doi: 10.1016/j.envpol.2021.116852 CrossRefGoogle ScholarPubMed
Zhou, J., Huang, N., Guo, Y., Cui, S., Ge, C., He, Q., Pan, X., Wang, G., Wang, H. and Hao, H. (2019). Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis. Acta Pharmaceutica Sinica. B, 9(3), 526–536. doi: 10.1016/j.apsb.2018.11.004 CrossRefGoogle ScholarPubMed