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Aging and gender-related effects of tauroursodeoxycholic acid treatment on liver functions, plasma lipid profile, and oxidative stress

Year 2022, Volume: 47 Issue: 1, 405 - 414, 31.03.2022
https://doi.org/10.17826/cumj.1023909

Abstract

Purpose: Aging is related to multiple and systemic dysfunctions in the body, accompanied by metabolic disorders and oxidative stress. Although studies are revealing the role of endoplasmic reticulum (ER) stress in aging-related pathologies, this relationship has not been fully elucidated. In this study, it was aimed to reveal changes in liver function, plasma lipids, and oxidative stress markers due to aging and gender, and to investigate how these parameters change with ER stress inhibitor tauro-ursodeoxycholic acid (TUDCA) treatment.
Materials and Methods: Young (4 months old) and old (24 months old) Wistar albino male and female rats were used in the experiments. The administration of ER stress inhibitor TUDCA was performed for 4 weeks (150 mg/kg/day, ip). Liver function markers (AST and ALT), plasma lipids (LDL, HDL, TG and total cholesterol), and oxidative stress biomarkers (malondialdehyde, (MDA) and myeloperoxidase (MPO)) levels were measured in plasma samples.
Results: ER stress inhibition with TUDCA decreased AST levels, increased HDL value, decreased TG value, and decreased MDA and MPO levels in the elderly. The effects on some parameters varied depending on gender.
Conclusion: Considering the role of oxidative stress and metabolic disorders in the pathogenesis of many age-related diseases, it is thought that these results will contribute to the development of treatment approaches targeting ER stress inhibition in aging.

References

  • Costantino S, Paneni F, Cosentino F. Ageing, metabolism and cardiovascular disease. J Physiol. 2016;594:2061-73.
  • Liu HH, Li JJ. Aging and dyslipidemia: a review of potential mechanisms. Ageing Res Rev. 2015;19:43-52.
  • Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020;41:111-188.
  • Yandrapalli S, Gupta S, Andries G, Cooper HA, Aronow WS. Drug therapy of dyslipidemia in the elderly. Drugs Aging. 2019;36:321-40.
  • Acharya P, Talahalli RR. Aging and hyperglycemia intensify dyslipidemia-induced oxidative stress and inflammation in rats: assessment of restorative potentials of ALA and EPA + DHA. Inflammation. 2019;42:946-952.
  • Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757-72.
  • Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov. 2021;20:689-709.
  • Taylor RC. Aging and the UPR(ER). Brain Res. 2016;1648:588-93.
  • Naidoo N. ER and aging-Protein folding and the ER stress response. Ageing Res Rev. 2009;8:150-9.
  • Brown MK, Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol. 2012;3:263.
  • Murray HC, Dieriks BV, Swanson MEV, Anekal PV, Turner C, Faull RLM et al. The unfolded protein response is activated in the olfactory system in Alzheimer's disease. Acta Neuropathol Com. 2020;8.
  • Sreedhar R, Giridharan VV, Arumugam S, Karuppagounder V, Palaniyandi SS, Krishnamurthy P et al. Role of MAPK-mediated endoplasmic reticulum stress signaling in the heart during aging in senescence-accelerated prone mice. Biofactors. 2016;42:368-75.
  • Sheedfar F, Di Biase S, Koonen D, Vinciguerra M. Liver diseases and aging: friends or foes? Aging Cell. 2013;12:950-54.
  • Nho K, Kueider-Paisley A, Ahmad S, MahmoudianDehkordi S, Arnold M, Risacher SL et al. Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA Netw Open. 2019;2:e197978.
  • Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. Can Med Assoc J. 2005;172:367-79.
  • Bedogni G, Gastaldelli A, Tiribelli C, Agosti F, De Col A, Fessehatsion R et al. Relationship between glucose metabolism and non-alcoholic fatty liver disease severity in morbidly obese women. J Endocrinol Invest. 2014;37:739-44.
  • Katsiki N, Perez-Martinez P, Anagnostis P, Mikhailidis DP, Karagiannis A. Is nonalcoholic fatty liver disease indeed the hepatic manifestation of metabolic syndrome? Curr Vasc Pharmacol. 2018;16:219-27.
  • Adeli K, Higgins V, Nieuwesteeg M, Raizman JE, Chen Y, Wong SL et al. Biochemical marker reference values across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. Clin Chem. 2015;61:1049-62.
  • Le Couteur DG, Blyth FM, Creasey HM, Handelsman DJ, Naganathan V, Sambrook PN et al. The association of alanine transaminase with aging, frailty, and mortality. J Gerontol A Biol Sci Med Sci. 2010;65:712-7.
  • Edvardsson M, Sund-Levander M, Milberg A, Wressle E, Marcusson J, Grodzinsky E. Differences in levels of albumin, ALT, AST, gamma-GT and creatinine in frail, moderately healthy and healthy elderly individuals. Clin Chem Lab Med. 2018;56:471-78.
  • Azman KF, Safdar A, Zakaria R. D-galactose-induced liver aging model: Its underlying mechanisms and potential therapeutic interventions. Exp Gerontol. 2021;150:111372.
  • Fu J, Zhang X, Chen P, Zhang Y. Endoplasmic reticulum stress is involved in 2,4-dichlorophenol-induced hepatotoxicity. J Toxicol Sci. 2016;41:745-56.
  • Pan XL, Zhao L, Li L, Li AH, Ye J, Yang L et al. Efficacy and safety of tauroursodeoxycholic acid in the treatment of liver cirrhosis: a double-blind randomized controlled trial. J Huazhong Univ Sci Technolog Med Sci. 2013;33:189-94.
  • Walter M. Interrelationships among HDL metabolism, aging, and atherosclerosis. Arterioscl Throm Vas. 2009;29:1244-50.
  • Ferrara A, Barrett-Connor E, Shan J. Total, LDL, and HDL cholesterol decrease with age in older men and women. The Rancho Bernardo Study 1984-1994. Circulation. 1997;96:37-43.
  • Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529:326-35.
  • Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69:927-47.
  • Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell. 2008;15:829-40.
  • Wang SY, Kaufman RJ. How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver? Curr Opin Lipidol. 2014;25:125-32.
  • Moldogazieva NT, Mokhosoev IM, Mel'nikova TI, Porozov YB, Terentiev AA. Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in Aging and Age-Related Diseases. Oxid Med Cell Longev. 2019;2019:3085756.
  • Papaconstantinou J. The role of signaling pathways of inflammation and oxidative stress in development of senescence and aging phenotypes in cardiovascular disease. Cells. 2019;8.
  • Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules. 2019;24.
  • Vatner SF, Zhang J, Oydanich M, Berkman T, Naftalovich R, Vatner DE. Healthful aging mediated by inhibition of oxidative stress. Ageing Res Rev. 2020;64:101194.
  • Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev. 2017;2017:6501046.
  • Ore A, Akinloye OA. Oxidative stress and antioxidant biomarkers in clinical and experimental models of non-alcoholic fatty liver disease. Medicina (Kaunas). 2019;55.
  • Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78:547-81.
  • Frijhoff J, Winyard PG, Zarkovic N, Davies SS, Stocker R, Cheng D et al. Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal. 2015;23:1144-70.
  • Kimura M, Yokoyama A, Higuchi S. Aldehyde dehydrogenase-2 as a therapeutic target. Expert Opin Ther Tar. 2019;23:955-66.
  • Zhao T, Wu K, Hogstrand C, Xu YH, Chen GH, Wei CC et al. Lipophagy mediated carbohydrate-induced changes of lipid metabolism via oxidative stress, endoplasmic reticulum (ER) stress and ChREBP/PPARgamma pathways. Cell Mol Life Sci. 2020;77:1987-2003.
  • Liu X, Zhang R, Huang L, Zheng Z, Vlassara H, Striker G et al. Excessive oxidative stress contributes to increased acute ER stress kidney injury in aged mice. Oxid Med Cell Longev. 2019;2019:2746521.

Tauroursodeoksikolik asit tedavisinin karaciğer fonksiyonları, plazma lipit profili ve oksidatif stres üzerindeki etkilerinin yaşlanmaya ve cinsiyete bağlı değişimi

Year 2022, Volume: 47 Issue: 1, 405 - 414, 31.03.2022
https://doi.org/10.17826/cumj.1023909

Abstract

Amaç: Yaşlanma vücutta çoklu ve sistemik işlev bozuklukları ile ilişkilidir, bu durumlara metabolizma bozuklukları ve oksidatif stres eşlik etmektedir. Endoplazmik retikulum (ER) stresinin yaşlanmaya bağlı patolojilerdeki rolünü gösteren çalışmalar olmakla birlikte bu ilişki tam olarak aydınlatılamamıştır. Bu çalışmada, karaciğer fonksiyonu, plazma lipitleri ve oksidatif stres belirteçlerinin yaşlanmaya ve cinsiyete bağlı değişimlerinin ortaya konması ayrıca bu parametrelerin ER stres inhibitörü tauro-ursodeoksikolik asit (TUDCA) tedavisiyle nasıl değiştiğinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: Deneylerde genç (4 aylık) ve yaşlı (24 aylık) Wistar albino erkek ve dişi sıçanlar kullanılmıştır. ER stres inhibitörü olarak TUDCA uygulaması 4 hafta süresince yapılmıştır (150 mg/kg/gün, ip). Plazma örneklerinde karaciğer fonksiyon belirteçleri (AST ve ALT), plazma lipitleri (LDL, HDL, TG ve total kolesterol) ve oksidatif stres biyobelirteçlerinin (malondialdehit, (MDA) ve miyeloperoksidaz (MPO)) seviyeleri ölçülmüştür..
Bulgular: Bu çalışmada TUDCA ile ER stres inhibisyonunun yaşlılarda AST seviyelerini azattığı, HDL değerini yükseltirken TG değerini düşürdüğü, MDA ve MPO düzeylerini azalttığı gösterilmiştir. Bazı parametreler üzerindeki etkileri cinsiyete bağlı olarak değişim göstermiştir.
Sonuç: Oksidatif stres ve metabolik bozuklukların yaşa bağlı pek çok hastalığın patogenezindeki rolü göz önüne alındığında; bu sonuçların yaşlanmada ER stres inhibisyonunu hedef alan tedavi yaklaşımlarının geliştirilmesine katkı sunacağı düşünülmektedir.

References

  • Costantino S, Paneni F, Cosentino F. Ageing, metabolism and cardiovascular disease. J Physiol. 2016;594:2061-73.
  • Liu HH, Li JJ. Aging and dyslipidemia: a review of potential mechanisms. Ageing Res Rev. 2015;19:43-52.
  • Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020;41:111-188.
  • Yandrapalli S, Gupta S, Andries G, Cooper HA, Aronow WS. Drug therapy of dyslipidemia in the elderly. Drugs Aging. 2019;36:321-40.
  • Acharya P, Talahalli RR. Aging and hyperglycemia intensify dyslipidemia-induced oxidative stress and inflammation in rats: assessment of restorative potentials of ALA and EPA + DHA. Inflammation. 2019;42:946-952.
  • Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757-72.
  • Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov. 2021;20:689-709.
  • Taylor RC. Aging and the UPR(ER). Brain Res. 2016;1648:588-93.
  • Naidoo N. ER and aging-Protein folding and the ER stress response. Ageing Res Rev. 2009;8:150-9.
  • Brown MK, Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol. 2012;3:263.
  • Murray HC, Dieriks BV, Swanson MEV, Anekal PV, Turner C, Faull RLM et al. The unfolded protein response is activated in the olfactory system in Alzheimer's disease. Acta Neuropathol Com. 2020;8.
  • Sreedhar R, Giridharan VV, Arumugam S, Karuppagounder V, Palaniyandi SS, Krishnamurthy P et al. Role of MAPK-mediated endoplasmic reticulum stress signaling in the heart during aging in senescence-accelerated prone mice. Biofactors. 2016;42:368-75.
  • Sheedfar F, Di Biase S, Koonen D, Vinciguerra M. Liver diseases and aging: friends or foes? Aging Cell. 2013;12:950-54.
  • Nho K, Kueider-Paisley A, Ahmad S, MahmoudianDehkordi S, Arnold M, Risacher SL et al. Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA Netw Open. 2019;2:e197978.
  • Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. Can Med Assoc J. 2005;172:367-79.
  • Bedogni G, Gastaldelli A, Tiribelli C, Agosti F, De Col A, Fessehatsion R et al. Relationship between glucose metabolism and non-alcoholic fatty liver disease severity in morbidly obese women. J Endocrinol Invest. 2014;37:739-44.
  • Katsiki N, Perez-Martinez P, Anagnostis P, Mikhailidis DP, Karagiannis A. Is nonalcoholic fatty liver disease indeed the hepatic manifestation of metabolic syndrome? Curr Vasc Pharmacol. 2018;16:219-27.
  • Adeli K, Higgins V, Nieuwesteeg M, Raizman JE, Chen Y, Wong SL et al. Biochemical marker reference values across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. Clin Chem. 2015;61:1049-62.
  • Le Couteur DG, Blyth FM, Creasey HM, Handelsman DJ, Naganathan V, Sambrook PN et al. The association of alanine transaminase with aging, frailty, and mortality. J Gerontol A Biol Sci Med Sci. 2010;65:712-7.
  • Edvardsson M, Sund-Levander M, Milberg A, Wressle E, Marcusson J, Grodzinsky E. Differences in levels of albumin, ALT, AST, gamma-GT and creatinine in frail, moderately healthy and healthy elderly individuals. Clin Chem Lab Med. 2018;56:471-78.
  • Azman KF, Safdar A, Zakaria R. D-galactose-induced liver aging model: Its underlying mechanisms and potential therapeutic interventions. Exp Gerontol. 2021;150:111372.
  • Fu J, Zhang X, Chen P, Zhang Y. Endoplasmic reticulum stress is involved in 2,4-dichlorophenol-induced hepatotoxicity. J Toxicol Sci. 2016;41:745-56.
  • Pan XL, Zhao L, Li L, Li AH, Ye J, Yang L et al. Efficacy and safety of tauroursodeoxycholic acid in the treatment of liver cirrhosis: a double-blind randomized controlled trial. J Huazhong Univ Sci Technolog Med Sci. 2013;33:189-94.
  • Walter M. Interrelationships among HDL metabolism, aging, and atherosclerosis. Arterioscl Throm Vas. 2009;29:1244-50.
  • Ferrara A, Barrett-Connor E, Shan J. Total, LDL, and HDL cholesterol decrease with age in older men and women. The Rancho Bernardo Study 1984-1994. Circulation. 1997;96:37-43.
  • Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529:326-35.
  • Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69:927-47.
  • Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell. 2008;15:829-40.
  • Wang SY, Kaufman RJ. How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver? Curr Opin Lipidol. 2014;25:125-32.
  • Moldogazieva NT, Mokhosoev IM, Mel'nikova TI, Porozov YB, Terentiev AA. Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in Aging and Age-Related Diseases. Oxid Med Cell Longev. 2019;2019:3085756.
  • Papaconstantinou J. The role of signaling pathways of inflammation and oxidative stress in development of senescence and aging phenotypes in cardiovascular disease. Cells. 2019;8.
  • Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules. 2019;24.
  • Vatner SF, Zhang J, Oydanich M, Berkman T, Naftalovich R, Vatner DE. Healthful aging mediated by inhibition of oxidative stress. Ageing Res Rev. 2020;64:101194.
  • Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev. 2017;2017:6501046.
  • Ore A, Akinloye OA. Oxidative stress and antioxidant biomarkers in clinical and experimental models of non-alcoholic fatty liver disease. Medicina (Kaunas). 2019;55.
  • Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78:547-81.
  • Frijhoff J, Winyard PG, Zarkovic N, Davies SS, Stocker R, Cheng D et al. Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal. 2015;23:1144-70.
  • Kimura M, Yokoyama A, Higuchi S. Aldehyde dehydrogenase-2 as a therapeutic target. Expert Opin Ther Tar. 2019;23:955-66.
  • Zhao T, Wu K, Hogstrand C, Xu YH, Chen GH, Wei CC et al. Lipophagy mediated carbohydrate-induced changes of lipid metabolism via oxidative stress, endoplasmic reticulum (ER) stress and ChREBP/PPARgamma pathways. Cell Mol Life Sci. 2020;77:1987-2003.
  • Liu X, Zhang R, Huang L, Zheng Z, Vlassara H, Striker G et al. Excessive oxidative stress contributes to increased acute ER stress kidney injury in aged mice. Oxid Med Cell Longev. 2019;2019:2746521.
There are 40 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research
Authors

Sevtap Han 0000-0001-6392-097X

Publication Date March 31, 2022
Acceptance Date February 17, 2022
Published in Issue Year 2022 Volume: 47 Issue: 1

Cite

MLA Han, Sevtap. “Aging and Gender-Related Effects of Tauroursodeoxycholic Acid Treatment on Liver Functions, Plasma Lipid Profile, and Oxidative Stress”. Cukurova Medical Journal, vol. 47, no. 1, 2022, pp. 405-14, doi:10.17826/cumj.1023909.