Study of the combined protective effect of adrenomedullin and exercise on induced fatty liver in male albino rats: A possible role of peroxisome proliferator-activated receptor-alpha

Alaa Saad Hassan El-lebiedy; Magdi Ali El-Damarawi; Enas Mohamed Al-Bendary; Romysaa Ali Elsherbini

doi:10.53730/ijhs.v9nS1.15756

Authors

Alaa Saad Hassan El-lebiedy
loala12345678@gmail.com
Tanta University, Tanta, Egypt
Magdi Ali El-Damarawi Tanta University, Tanta, Egypt
Enas Mohamed Al-Bendary Tanta University, Tanta, Egypt
Romysaa Ali Elsherbini Tanta University, Tanta, Egypt

Keywords:

Induced Fatty Liver, Adrenomedullin, Peroxisome Proliferator-Activated Receptor-Alpha, Male Albino Rats

Abstract

Background: Adrenomedullin (AM) is a key antioxidant and anti-inflammatory agent vital for disease prevention throughout the body, while regular physical exercise helps prevent severe obesity and related complications like non-alcoholic fatty liver (NAFL). This study aimed to evaluate the protective effects of AM and regular exercise on fatty liver disease (FLD). Methods: This study involved 50 male rats divided into five groups: Group I received a normal diet for 8 weeks (control), Group II was given a high-fat high-cholesterol diet (HFHCD) to induce fatty liver, Group III received HFHCD plus daily subcutaneous adrenomedullin (50 ng/kg) for 8 weeks, Group IV received HFHCD plus moderate swimming exercise (1 hour/day, 5 days/week) for 6 weeks, and Group V received HFHCD along with both AM and exercise for 8 weeks. Results: In fatty liver-induced rats (GII): serum liver enzymes, lipid profile, hepatic MDA and NF-κB levels significantly increased, while hepatic PPAR-α and TAC significantly decreased compared to controls (GI). Treatment with A.M (GIII), exercise (GIV), or both (GV) significantly reversed these effects. GV showed the most improvement but not fully restoring levels to those of GI. Conclusions: AM and regular exercise together protect against FLD by reducing inflammation, fat content and liver damage.

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References

Abarikwu, S. O., Farombi, E. O. & Pant, A. B. (2012). Kolaviron biflavanoids of Garcinia kola seeds protect atrazine-induced cytotoxicity in primary cultures of rat Leydig cells. Int J Toxicol, 31, 407-15. DOI: https://doi.org/10.1177/1091581812445476

Abd-Ellatif, R. N., Nasef, N. A., El-Horany, H. E., Emam, M. N., Younis, R. L., El Gheit, R. E. A., Elseady, W., Radwan, D. A., Hafez, Y. M., Eissa, A., Aboalsoud, A., Shalaby, R. H. & Atef, M. M. (2022). Adrenomedullin mitigates doxorubicin-induced nephrotoxicity in rats: Role of oxidative stress, inflammation, apoptosis, and pyroptosis. Int J Mol Sci, 23, 155. DOI: https://doi.org/10.3390/ijms232314570

Anstee, Q. M., Targher, G. & Day, C. P. (2013). Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol, 10, 330-44. DOI: https://doi.org/10.1038/nrgastro.2013.41

Argo, C. K. & Caldwell, S. H. (2009). Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis, 13, 511-31. DOI: https://doi.org/10.1016/j.cld.2009.07.005

Artiss, J. (2000). Measurement of cholesterol concentration. Handbook of lipoprotein testing, 45, 189-205.

Bacchi, E., Negri, C., Targher, G., Faccioli, N., Lanza, M., Zoppini, G., Zanolin, E., Schena, F., Bonora, E. & Moghetti, P. (2013). Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology, 58, 1287-95. DOI: https://doi.org/10.1002/hep.26393

Berger, J., Leibowitz, M. D., Doebber, T. W., Elbrecht, A., Zhang, B., Zhou, G., Biswas, C., Cullinan, C. A., Hayes, N. S., Li, Y., Tanen, M., Ventre, J., Wu, M. S., Berger, G. D., Mosley, R., Marquis, R., Santini, C., Sahoo, S. P., Tolman, R. L., Smith, R. G. & Moller, D. E. (1999). Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem, 274, 6718-25. DOI: https://doi.org/10.1074/jbc.274.10.6718

Catoire, M. & Kersten, S. (2015). The search for exercise factors in humans. Faseb j, 29, 1615-28. DOI: https://doi.org/10.1096/fj.14-263699

Chau, J. Y., Grunseit, A. C., Chey, T., Stamatakis, E., Brown, W. J., Matthews, C. E., Bauman, A. E. & Van Der Ploeg, H. P. (2013). Daily sitting time and all-cause mortality: a meta-analysis. PloS one, 11, 80000. DOI: https://doi.org/10.1371/journal.pone.0080000

Chevenne, D., Ruiz, J., Lohmann, L., Laudat, A., Leblanc, H., Gray, I. P., Passa, P. & Porquet, D. (1994). Immunoradiometric assay of human intact proinsulin applied to patients with type 2 diabetes, impaired glucose tolerance, and hyperandrogenism. Clin Chem, 40, 754-7. DOI: https://doi.org/10.1093/clinchem/40.5.754

Diamond, M. P., Chauhan, S., Kruger, M. & Subramanian, M. (2003). Values of fasting glucose levels, glucose tolerance tests, and glucose-insulin ratios as predictors of glucose tolerance. Fertil Steril, 80, 1022-5. DOI: https://doi.org/10.1016/S0015-0282(03)01016-1

ElGendy, A. A., Elsaed, W. M., Elaziz, H. A. & Ahmed, A. (2019). Effect of adrenomedullin and omega-3 polyunsaturated fatty acids on celecoxib - induced acute hepatic injury in experimental rats. Bull Egypt Soc Physiol Sci, 39, 252-70. DOI: https://doi.org/10.21608/besps.2019.13769.1022

Elmarakby, A. A. & Imig, J. D. (2010). Obesity is the major contributor to vascular dysfunction and inflammation in high-fat diet hypertensive rats. Clin Sci (Lond), 118, 291-301. DOI: https://doi.org/10.1042/CS20090395

Farzanegi, P., Dana, A., Ebrahimpoor, Z., Asadi, M. & Azarbayjani, M. A. (2019). Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): Roles of oxidative stress and inflammation. Eur J Sport Sci, 19, 994-1003. DOI: https://doi.org/10.1080/17461391.2019.1571114

Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. (2018). Mechanisms of NAFLD development and therapeutic strategies. Nat Med, 24, 908-22. DOI: https://doi.org/10.1038/s41591-018-0104-9

Golbidi, S., Badran, M. & Laher, I. (2012). Antioxidant and anti-inflammatory effects of exercise in diabetic patients. Exp Diabetes Res, 2012, 941868. DOI: https://doi.org/10.1155/2012/941868

Hellenthal, K. E. M., Brabenec, L. & Wagner, N. M. (2022). Regulation and dysregulation of endothelial permeability during systemic inflammation. Cells, 12, 159. DOI: https://doi.org/10.3390/cells11121935

Ipsen, D. H., Lykkesfeldt, J. & Tveden-Nyborg, P. (2018). Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci, 75, 3313-27. DOI: https://doi.org/10.1007/s00018-018-2860-6

Keating, S. E., Hackett, D. A., Parker, H. M., Way, K. L., O'Connor, H. T., Sainsbury, A., Baker, M. K., Chuter, V. H., Caterson, I. D. & George, J. (2017). Effect of resistance training on liver fat and visceral adiposity in adults with obesity: a randomized controlled trial. Hepatol Res, 47, 622-31. DOI: https://doi.org/10.1111/hepr.12781

Kersten, S. & Stienstra, R. (2017). The role and regulation of the peroxisome proliferator activated receptor alpha in human liver. Biochimie, 136, 75-84. DOI: https://doi.org/10.1016/j.biochi.2016.12.019

Kim, K. S., Hong, S., Han, K. & Park, C. Y. (2024). Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study. Bmj, 384, 076388. DOI: https://doi.org/10.1136/bmj-2023-076388

Kita, T. & Kitamura, K. (2022). Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases. Hypertens Res, 45, 389-400. DOI: https://doi.org/10.1038/s41440-021-00806-y

Krzeminski, K. (2016). The role of adrenomedullin in cardiovascular response to exercise–a review. Journal of human kinetics, 53, 127. DOI: https://doi.org/10.1515/hukin-2016-0017

Linscheid, P., Seboek, D., Zulewski, H., Keller, U. & Muller, B. (2005). Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology, 146, 2699-708. DOI: https://doi.org/10.1210/en.2004-1424

Liu, Y., Deguchi, Y., Tian, R., Wei, D., Wu, L., Chen, W., Xu, W., Xu, M., Liu, F., Gao, S., Jaoude, J. C., Chrieki, S. P., Moussalli, M. J., Gagea, M., Morris, J., Broaddus, R. R., Zuo, X. & Shureiqi, I. (2019). Pleiotropic effects of PPARD accelerate colorectal tumorigenesis, progression, and invasion. Cancer Res, 79, 954-69. DOI: https://doi.org/10.1158/0008-5472.CAN-18-1790

Llovet, J. M., Willoughby, C. E., Singal, A. G., Greten, T. F., Heikenwälder, M., El-Serag, H. B., Finn, R. S. & Friedman, S. L. (2023). Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol, 20, 487-503. DOI: https://doi.org/10.1038/s41575-023-00754-7

Mantena, S. K., Vaughn, D. P., Andringa, K. K., Eccleston, H. B., King, A. L., Abrams, G. A., Doeller, J. E., Kraus, D. W., Darley-Usmar, V. M. & Bailey, S. M. (2009). High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem J, 417, 183-93. DOI: https://doi.org/10.1042/BJ20080868

Martin, K., Hatab, A., Athwal, V. S., Jokl, E. & Piper Hanley, K. (2021). Genetic contribution to non-alcoholic fatty liver disease and prognostic implications. Curr Diab Rep, 21, 8. DOI: https://doi.org/10.1007/s11892-021-01377-5

McGowan, M. W., Artiss, J. D., Strandbergh, D. R. & Zak, B. (1983). A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem, 29, 538-42. DOI: https://doi.org/10.1093/clinchem/29.3.538

Mustafa, H. N., El Awdan, S. A. & Hegazy, G. A. (2013). Protective role of antioxidants on thioacetamide-induced acute hepatic encephalopathy: biochemical and ultrastructural study. Tissue Cell, 45, 350-62. DOI: https://doi.org/10.1016/j.tice.2013.06.001

MY Cheung, B. & Tang, F. (2012). Adrenomedullin: exciting new horizons. Recent patents on endocrine, metabolic & immune drug discovery, 6, 4-17. DOI: https://doi.org/10.2174/187221412799015263

Nascimento, A. F., Sugizaki, M. M., Leopoldo, A. S., Lima-Leopoldo, A. P., Luvizotto, R. A., Nogueira, C. R. & Cicogna, A. C. (2008). A hypercaloric pellet-diet cycle induces obesity and co-morbidities in Wistar rats. Arq Bras Endocrinol Metabol, 52, 968-74. DOI: https://doi.org/10.1590/S0004-27302008000600007

Ni, Y. G., Condra, J. H., Orsatti, L., Shen, X., Di Marco, S., Pandit, S., Bottomley, M. J., Ruggeri, L., Cummings, R. T., Cubbon, R. M., Santoro, J. C., Ehrhardt, A., Lewis, D., Fisher, T. S., Ha, S., Njimoluh, L., Wood, D. D., Hammond, H. A., Wisniewski, D., Volpari, C., Noto, A., Lo Surdo, P., Hubbard, B., Carfí, A. & Sitlani, A. (2010). A proprotein convertase subtilisin-like/kexin type 9 (PCSK9) C-terminal domain antibody antigen-binding fragment inhibits PCSK9 internalization and restores low density lipoprotein uptake. J Biol Chem, 285, 12882-91. DOI: https://doi.org/10.1074/jbc.M110.113035

Oba, S., Hino, M. & Fujita, T. (2008). Adrenomedullin protects against oxidative stress-induced podocyte injury as an endogenous antioxidant. Nephrol Dial Transplant, 23, 510-7. DOI: https://doi.org/10.1093/ndt/gfm600

Orci, L. A., Gariani, K., Oldani, G., Delaune, V., Morel, P. & Toso, C. (2016). Exercise-based interventions for nonalcoholic fatty liver disease: a meta-analysis and meta-regression. Clin Gastroenterol Hepatol, 14, 1398-411. DOI: https://doi.org/10.1016/j.cgh.2016.04.036

Palipoch, S. & Punsawad, C. (2013). Biochemical and histological study of rat liver and kidney injury induced by Cisplatin. J Toxicol Pathol, 26, 293-9. DOI: https://doi.org/10.1293/tox.26.293

Passaglia, P., Gonzaga, N. A., Tirapelli, D. P., Tirapelli, L. F. & Tirapelli, C. R. (2014). Pharmacological characterisation of the mechanisms underlying the relaxant effect of adrenomedullin in the rat carotid artery. J Pharm Pharmacol, 66, 1734-46. DOI: https://doi.org/10.1111/jphp.12299

Petrakis, D., Vassilopoulou, L., Mamoulakis, C., Psycharakis, C., Anifantaki, A., Sifakis, S., Docea, A. O., Tsiaoussis, J., Makrigiannakis, A. & Tsatsakis, A. M. (2017). Endocrine disruptors leading to obesity and related diseases. Int J Environ Res Public Health, 14, 69. DOI: https://doi.org/10.3390/ijerph14101282

Pintér, E., Pozsgai, G., Hajna, Z., Helyes, Z. & Szolcsányi, J. (2014). Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions. Br J Clin Pharmacol, 77, 5-20. DOI: https://doi.org/10.1111/bcp.12097

Qian, P., Wang, Q., Wang, F.-Z., Dai, H.-B., Wang, H.-Y., Gao, Q., Zhou, H. & Zhou, Y.-B. (2022). Adrenomedullin improves cardiac remodeling and function in obese rats with hypertension. Pharmaceuticals, 15, 719. DOI: https://doi.org/10.3390/ph15060719

Rabøl, R., Petersen, K. F., Dufour, S., Flannery, C. & Shulman, G. I. (2011). Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A, 108, 13705-9. DOI: https://doi.org/10.1073/pnas.1110105108

Rezaei-Moghadam, A., Mohajeri, D., Rafiei, B., Dizaji, R., Azhdari, A., Yeganehzad, M., Shahidi, M. & Mazani, M. (2012). Effect of turmeric and carrot seed extracts on serum liver biomarkers and hepatic lipid peroxidation, antioxidant enzymes and total antioxidant status in rats. Bioimpacts, 2, 151-7.

Rinella, M. & Charlton, M. (2016). The globalization of nonalcoholic fatty liver disease: Prevalence and impact on world health. Hepatology, 64, 19-22. DOI: https://doi.org/10.1002/hep.28524

Rodríguez-Sureda, V. & Peinado-Onsurbe, J. (2005). A procedure for measuring triacylglyceride and cholesterol content using a small amount of tissue. Anal Biochem, 343, 277-82. DOI: https://doi.org/10.1016/j.ab.2005.05.009

Sacco, M. A., Gualtieri, S., Cordasco, F., Tarallo, A. P., Verrina, M. C., Princi, A., Bruni, A., Garofalo, E. & Aquila, I. (2024). The role of adrenomedullin as a predictive marker of the risk of death and adverse clinical events: A review of the literature. J. Clin. Med, 16, 4847. DOI: https://doi.org/10.3390/jcm13164847

Schuetz, P., Marlowe, R. J. & Mueller, B. (2015). The prognostic blood biomarker proadrenomedullin for outcome prediction in patients with chronic obstructive pulmonary disease (COPD): a qualitative clinical review. Clin Chem Lab Med, 53, 521-39. DOI: https://doi.org/10.1515/cclm-2014-0748

Shekarforoush, S., Fatahi, Z. & Safari, F. (2016). The effects of pentobarbital, ketamine-pentobarbital and ketamine-xylazine anesthesia in a rat myocardial ischemic reperfusion injury model. Lab Anim, 50, 179-84. DOI: https://doi.org/10.1177/0023677215597136

Souza, M. A., Oliveira, M. S., Furian, A. F., Rambo, L. M., Ribeiro, L. R., Lima, F. D., Dalla Corte, L. C., Silva, L. F., Retamoso, L. T., Dalla Corte, C. L., Puntel, G. O., de Avila, D. S., Soares, F. A., Fighera, M. R., de Mello, C. F. & Royes, L. F. (2009). Swimming training prevents pentylenetetrazol-induced inhibition of Na+, K+-ATPase activity, seizures, and oxidative stress. Epilepsia, 50, 811-23. DOI: https://doi.org/10.1111/j.1528-1167.2008.01908.x

Wang, H. Y., Wang, F. Z., Chang, R., Wang, Q., Liu, S. Y., Cheng, Z. X., Gao, Q., Zhou, H. & Zhou, Y. B. (2023). Adrenomedullin improves hypertension and vascular remodeling partly through the receptor-mediated ampk pathway in rats with obesity-related hypertension. Int J Mol Sci, 24, 48. DOI: https://doi.org/10.3390/ijms24043943

Xu, Z. J., Fan, J. G., Ding, X. D., Qiao, L. & Wang, G. L. (2010). Characterization of high-fat, diet-induced, non-alcoholic steatohepatitis with fibrosis in rats. Dig Dis Sci, 55, 931-40. DOI: https://doi.org/10.1007/s10620-009-0815-3

Ye, J. & Liu, X. (2022). Interactions between endoplasmic reticulum stress and extracellular vesicles in multiple diseases. Front Immunol, 13, 955419. DOI: https://doi.org/10.3389/fimmu.2022.955419

Yildirim, N. & Yurekli, M. (2010). The effect of adrenomedullin and cold stress on interleukin-6 levels in some rat tissues. Clin Exp Immunol, 161, 171-5. DOI: https://doi.org/10.1111/j.1365-2249.2010.04156.x

Yoshimoto, T. & Hirata, Y. (2005). Adrenomedullin receptor and signal transduction. Adrenomedullin in cardiovascular disease. Springer. 17-40. DOI: https://doi.org/10.1007/0-387-25405-6_2

Younossi, Z. M., Golabi, P., Paik, J. M., Henry, A., Van Dongen, C. & Henry, L. (2023). The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 77, 1335-47. DOI: https://doi.org/10.1097/HEP.0000000000000004