Fructose Consumption Causes Cell Death through ER Stress in Pancreas and Changes Biochemical Parameters in Blood

Öz

Fructose is the natural sugar found in fruits. This sugar is widely used in all ready-made foods, especially in soft drinks. The study aims to examine how fructose consumption affects biochemical parameters in blood and whether it causes endoplasmic reticulum (ER) stress-caused cell death in pancreatic tissue. Sprague-Dawley rats were separated into control and fructose groups. Control animals (n=7) had free access to tap water, and standard pellet, fructose group (n=7) was given 20% fructose in drinking water for eight weeks. The consumption of food and fluid of the rats were measured daily during the experiment. The lipid levels and total oxidant/antioxidant statuses in serum were analyzed. Grp-78, IRE1-α, PERK, ATF-4, and -6, CHOP, and Caspase (Cas)-3/-8/-9/-12 mRNA expression levels in pancreas were detected. Fructose intake increased TG and VLDL levels in serum, and the mRNA expression levels of Grp-78, IRE-1α, PERK, ATF-4, -6 and Cas-3/-8/-9/-12 in pancreas with fructose consumption as compared with control group. Fructose consumption may cause disruption of lipid profile and oxidant/antioxidant balance, as well as trigger ER stress and thus cause programmed cell death. This will lead to the development of many diseases.

Anahtar Kelimeler

• Apoptosis
• cell death
• ER stress
• fructose
• oxidative stress

Fruktoz Tüketimi Pankreasta Endoplazmik Retikulum Stresi Yoluyla Hücre Ölümüne Neden Olur ve Kandaki Biyokimyasal Parametreleri Değiştirir

Öz

Fruktoz meyvelerde bulunan doğal bir şekerdir. Bu şeker, başta meşrubatlar olmak üzere tüm hazır gıdalarda yaygın olarak kullanılmaktadır. Bu çalışma, fruktoz tüketiminin kandaki biyokimyasal parametreleri nasıl etkilediğini ve pankreas dokusunda endoplazmik retikulum (ER) stres kaynaklı hücre ölümüne neden olup olmadığını araştırmayı amaçlamaktadır. Sprague-Dawley sıçanlar iki gruba ayrıldı. Kontrol grubu (n=7) standart pelet ve çeşme suyu ile beslendi, fruktoz grubunun (n=7) içme suyuna %20 fruktoz 8 hafta boyunca eklendi. Deney süresince sıçanların günlük yem ve sıvı tüketimleri ölçüldü. Serumdaki lipid seviyeleri ve toplam oksidan/antioksidan durumları analiz edildi. Pankreas dokusunda Grp-78, IRE1-α, PERK, ATF-4 ve -6, CHOP, Caspase-3, -8, -9 ve -12 mRNA ekspresyon seviyeleri tespit edildi. Kontrol grubu ile karşılaştırıldığında fruktoz tüketimi, serumda TG ve VLDL düzeylerini ve fruktozlu sıçan pankreasında Grp-78, IRE-1α, PERK, ATF-4, -6 ve Kaspaz-3, -8, -9 ve -12 mRNA ekspresyon düzeylerini artırdı. Fruktoz tüketimi lipid profilinin ve oksidan/antioksidan dengesinin bozulmasına neden olabileceği gibi ER stresini tetikleyerek programlı hücre ölümüne neden olabilir. Bu, birçok hastalığın gelişmesine yol açacaktır.

Anahtar Kelimeler

• Apoptoz
• hücre ölümü
• ER stresi
• fruktoz
• oksidatif stres

Kaynakça

1. [1] Bray, G.A. (2008). Fructose: should we worry? International Journal of Obesity, 32, 127-131.
2. [2] Khorshidian, N., Shadnoush, M., Zabihzadeh Khajavi, M., Sohrabvandi, S., Yousefi, M., Mortazavian, A.M. (2021). Fructose and high fructose corn syrup: are they a two-edged sword? International Journal of Food Sciences & Nutrition, 72, 592-614.
3. [3] Stanhope, K.L., Havel, P.J. (2008). Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance. Current Opinion in Lipidology, 19, 16-24.
4. [4] Tappy, L., Lê, K.A. (2010). Metabolic effects of fructose and the worldwide increase in obesity. Physiological Reviews, 90, 23-46.
5. [5] Erkelens, D.W. (2001). Insulin resistance syndrome and type 2 diabetes mellitus. American Journal of Cardiology, 88, 38J-42J.
6. [6] Grundy, S.M. (2012). Pre-diabetes, metabolic syndrome, and cardiovascular risk. Journal of the American College of Cardiology, 59, 635-643.
7. [7] Fernandes-da-Silva, A., Miranda, C.S., Santana-Oliveira, D.A., Oliveira-Cordeiro, B., Rangel-Azevedo, C., Silva-Veiga, F.M., Martins, F.F., Souza-Mello, V. (2021). Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas. European Journal of Nutrition, 60, 2949-2960.
8. [8] Hagenlocher, C., Siebert, R., Taschke, B., Wieske, S., Hausser, A., Rehm, M. (2022). ER stress-induced cell death proceeds independently of the TRAIL-R2 signaling axis in pancreatic β cells. Cell Death Discovery, 8, 34.

9. [9] Wang, W.A., Groenendyk, J., Michalak, M. (2014). Endoplasmic reticulum stress associated responses in cancer. Biochimica et Biophysica Acta, 1843, 2143-2149.
10. [10] Kanter, M., Aktas, C., Erboga, M. (2012). Protective effects of quercetin against apoptosis and oxidative stress in streptozotocin-induced diabetic rat testis. Food & Chemical Toxicology, 50, 719-725.
11. [11] Long, L., Wang, J., Lu, X., Xu, Y., Zheng, S., Luo, C., Li, Y. (2015). Protective effects of scutellarin on type II diabetes mellitus-induced testicular damages related to reactive oxygen species/Bcl-2/Bax and reactive oxygen species/microcirculation/staving pathway in diabetic rat. Journal of Diabetes Research, 2015, 252530.
12. [12] Bagul, P.K., Middela, H., Matapally, S., Padiya, R., Bastia, T., Madhusudana, K., Reddy, B.R., Chakravarty, S., Banerjee, S.K. (2012). Attenuation of insulin resistance, metabolic syndrome and hepatic oxidative stress by resveratrol in fructose-fed rats. Pharmacological Research, 66, 260-268.
13. [13] Crescenzo, R., Bianco, F., Falcone, I., Coppola, P., Liverini, G., Iossa, S. (2013). Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. European Journal of Nutrition, 52, 537-545.
14. [14] Ledwozyw, A., Michalak, J., Stepień, A., Kadziołka, A. (1986). The relationship between plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clinica Chimica Acta, 155, 275-283.
15. [15] Sangüesa, G., Roglans, N., Montañés, J.C., Baena, M., Velázquez, A.M., Sánchez, R.M., Alegret, M., Laguna, J.C. (2018). Chronic liquid fructose, but not glucose, supplementation selectively induces visceral adipose tissue leptin resistance and hypertrophy in female sprague-dawley rats. Molecular Nutrition & Food Research, 27: e1800777.
16. [16] Ramos, V.W., Batista, L.O., Albuquerque, K.T. (2017). Effects of fructose consumption on food intake and biochemical and body parameters in Wistar rats. Revista Portuguesa de Cardiologia, 36, 937-941.
17. [17] Ohashi, K., Ohta, Y., Ishikawa, H., Kitagawa, A. (2021). Orally administered octacosanol improves some features of high fructose-induced metabolic syndrome in rats. Journal of Clinical Biochemistry & Nutrition, 68, 58-66.
18. [18] Aguilera-Mendez, A., Hernández-Equihua, M.G., Rueda-Rocha, A.C., Guajardo-López, C., Nieto-Aguilar, R., Serrato-Ochoa, D., Ruíz Herrera, L.F., Guzmán-Nateras, J.A. (2018). Protective effect of supplementation with biotin against high-fructose-induced metabolic syndrome in rats. Nutritional Research, 57, 86-96.
19. [19] Abdelmoneim, D., El-Adl, M., El-Sayed, G., El-Sherbini, E.S. (2021). Protective effect of fenofibrate against high-fat-high-fructose diet induced non-obese NAFLD in rats. Fundamental & Clinical Pharmacology, 35, 379-388.
20. [20] Mamikutty, N., Thent, Z.C., Haji Suhaimi, F. (2015). Fructose-drinking water induced nonalcoholic fatty liver disease and ultrastructural alteration of hepatocyte mitochondria in male Wistar rat. Biomed Research International, 2015, 895961-895967.
21. [21] Li, L., Fang, B., Zhang, Y., Yan, L., He, Y., Hu, L., Xu, Q., Li, Q., Dai, X., Kuang, Q., Xu, M., Tan, J., Ge, C. (2022). Carminic acid mitigates fructose-triggered hepatic steatosis by inhibition of oxidative stress and inflammatory reaction. Biomedicine & Pharmacotherapy, 145, 112404.
22. [22] Malhotra, J.D., Miao, H., Zhang, K., Wolfson, A., Pennathur, S., Pipe, S.W., Kaufmana, R.J. (2008). Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proceeding of the National Academy of Sciences, 105, 18525-18530.
23. [23] Ajiboye, T.O., Hussaini, A.A., Nafiu, B.Y., Ibitoye, O.B. (2017). Aqueous seed extract of Hunteria umbellata (K. Schum.) Hallier f. (Apocynaceae) palliates hyperglycemia, insulin resistance, dyslipidemia, inflammation and oxidative stress in high-fructose diet-induced metabolic syndrome in rats. Journal of Ethnopharmacology, 198, 184-193.
24. [24] Ibitoye, O.B., Ajiboye, T.O. (2018). Dietary phenolic acids reverse insulin resistance, hyperglycaemia, dyslipidaemia, inflammation and oxidative stress in high-fructose diet-induced metabolic syndrome rats. Archives of Physiology & Biochemistry, 124, 410-417.
25. [25] Kelany, M.E., Hakami, T.M., Omar, A.H. (2017). Curcumin improves the metabolic syndrome in high-fructose-diet-fed rats: role of TNF-α, NF-κB, and oxidative stress. Canadian Journal of Physiology & Pharmacology, 95, 140-150.
26. [26] Scheuner, D., Song, B., McEwen, E., Liu, C., Laybutt, R., Gillespie, P., Saunders, T., Bonner-Weir, S., Kaufman, R.J. (2001). Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Molecular Cell, 7, 1165-1176.
27. [27] Harding, H.P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D.D., Ron, D. (2001). Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Molecular Cell, 7, 1153-1163.
28. [28] Akiyama, M., Liew, C.W., Lu, S., Hu, J., Martinez, R., Hambro, B., Kennedy, R.T., Kulkarni, R.N. (2013). X-box binding protein 1 is essential for insulin regulation of pancreatic α-cell function. Diabetes, 62, 2439-2449.
29. [29] Sundar Rajan, S., Srinivasan, V., Balasubramanyam, M., Tatu, U. (2007). Endoplasmic reticulum (ER) stress & diabetes. Indian Journal of Medical Research, 125, 411-424.
30. [30] Balakumar, M., Raji, L., Prabhu, D., Sathishkumar, C., Prabu, P., Mohan, V., Balasubramanyam, M. (2016). High-fructose diet is as detrimental as high-fat diet in the induction of insulin resistance and diabetes mediated by hepatic/pancreatic endoplasmic reticulum (ER) stress. Molecular & Cellular Biochemistry, 423, 93-104.
31. [31] Thameem, F., Farook, V.S., Bogardus, C., Prochazka, M. (2006). Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes, 55, 839-842.
32. [32] Meex, S.J., van Greevenbroek, M.M., Ayoubi, T.A., Vlietinck, R., van Vliet-Ostaptchouk, J.V., Hofker, M.H., Vermeulen, V.M., Schalkwijk, C.G., Feskens, E.J., Boer, J.M., Stehouwer, C.D., van der Kallen, C.J., de Bruin, T.W. (2007). Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians. Journal of Clinical Endocrinology & Metabolism, 92, 2720-2725.
33. [33] Back, S.H., Kang, S.W., Han, J., Chung, H.T. (2012). Endoplasmic reticulum stress in the β-cell pathogenesis of type 2 diabetes. Experimental Diabetes Research, 2012, 618396.
34. [34] Szegezdi, E., Fitzgerald, U., Samali, A. (2003). Caspase-12 and ER-stress-mediated apoptosis: the story so far. Annals of the New York Academy of Sciences, 1010, 186-194.
35. [35] Szegezdi, E., Logue, S.E., Gorman, A.M., Samali, A. (2006). Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Reports, 7, 880-885.
36. [36] Chen, X., Fu, X.S., Li, C.P., Zhao, H.X. (2014). ER stress and ER stress-induced apoptosis are activated in gastric SMCs in diabetic rats. World Journal of Gastroenterology, 20, 8260-8267.
37. [37] Riedl, S.J., Shi, Y. (2004). Molecular mechanisms of caspase regulation during apoptosis. Nature Reviews Molecular Cell Biology, 5, 897-907.
38. [38] Cheng, S.M., Cheng, Y.J., Wu, L.Y., Kuo, C.H., Lee, Y.S., Wu, M.C., Huang, C.Y., Ting, H., Lee, S.D. (2014). Activated apoptotic and anti-survival effects on rat hearts with fructose induced metabolic syndrome. Cell Biochemistry & Function, 32, 133-141.
39. [39] Kalra, J., Mangali, S.B., Bhat, A., Dhar, I., Udumula, M.P., Dhar, A. (2018). Imoxin attenuates high fructose-induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway. Fundamental & Clinical Pharmacology, 32, 297-305.