Abstract
Safety concerns have been raised regarding the association of chronic consumption of artificial sweeteners (ASs) with metabolic disorders, especially in the heart and brain. There has been no information on the in vivo physiological effects of AS consumption in lipoprotein metabolism. High-dosage treatment (final 25, 50, and 100 mM) with AS (aspartame, acesulfame K, and saccharin) to human high-density lipoprotein (HDL) induced loss of antioxidant ability along with elevated atherogenic effects. Aspartame-treated HDL3 (final 100 mM) almost all disappeared due to putative proteolytic degradation. Aspartame- and saccharin-treated HDL3 showed more enhanced cholesteryl ester transfer activity, while their antioxidant ability was disappeared. Microinjection of the modified HDL3 exacerbated the inflammatory death in zebrafish embryos in the presence of oxLDL. These results show that AS treatment impaired the beneficial functions of HDL, resulting in loss of antioxidant and anti-atherogenic activities. These results suggest that aspartame and saccharin could be toxic to the human circulation system as well as embryonic development via impairment of lipoprotein function.
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Bandyopadhyay, A., Ghoshal, S., & Mukherjee, A. (2008). Genotoxicity testing of low-calorie sweeteners: Aspartame, acesulfame-K, and saccharin. Drug and Chemical Toxicology, 31, 447–457.
Olney, J. W., Farber, N. B., Spitznagel, E., & Robins, L. N. (1996). Increasing brain tumor rates: Is there a link to aspartame? Journal of Neuropathology and Experimental Neurology, 55, 1115–1123.
Jang, W., Jeoung, N. H., & Cho, K. H. (2011). Modified apolipoprotein (apo) A-I by artificial sweetener causes severe premature cellular senescence and atherosclerosis with impairment of functional and structural properties of apoA-I in lipid-free and lipid-bound state. Molecules and Cells, 31, 461–470.
Kim, J. Y., Seo, J., & Cho, K. H. (2011). Aspartame-fed zebrafish exhibit acute deaths with swimming defects and saccharin-fed zebrafish have elevation of cholesteryl ester transfer protein activity in hypercholesterolemia. Food and Chemical Toxicology, 49, 2899–2905.
Cho, K. H. (2009). Synthesis of reconstituted high density lipoprotein (rHDL) containing apoA-I and apoC-III: The functional role of apoC-III in rHDL. Molecules and Cells, 27, 291–297.
Rye, K. A., & Barter, P. J. (2008). Antiinflammatory actions of HDL: A new insight. Arteriosclerosis, Thrombosis, and Vascular Biology, 28, 1890–1891.
Park, K. H., Jang, W., Kim, K. Y., Kim, J. R., & Cho, K. H. (2010). Fructated apolipoprotein A-I showed severe structural modification and loss of beneficial functions in lipid-free and lipid-bound state with acceleration of atherosclerosis and senescence. Biochemical and Biophysical Research Communications, 392, 295–300.
Roberts, H. J. (2003). Aspartame disease: An ignored epidemic. Ontario: Sunshine Sentinel Press.
Selderslaghs, I. W., Blust, R., & Witters, H. E. (2012). Feasibility study of the zebrafish assay as an alternative method to screen for developmental toxicity and embryotoxicity using a training set of 27 compounds. Reproductive Toxicology, 33, 142–154.
Selderslaghs, I. W., Van Rompay, A. R., De Coen, W., & Witters, H. E. (2009). Development of a screening assay to identify teratogenic and embryotoxic chemicals using the zebrafish embryo. Reproductive Toxicology, 28, 308–320.
Havel, R. J., Eder, H. A., & Bragdon, J. H. (1955). The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. The Journal of Clinical Investigation, 34, 1345–1353.
Markwell, M. A., Haas, S. M., Bieber, L. L., & Tolbert, N. E. (1978). A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Analytical Biochemistry, 87, 206–210.
Benzie, I. F., & Strain, J. J. (1996). The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Analytical Biochemistry, 239, 70–76.
Eckerson, H. W., Wyte, C. M., & La Du, B. N. (1983). The human serum paraoxonase/arylesterase polymorphism. American Journal of Human Genetics, 35, 1126–1238.
Esterbauer, H., Striegl, G., Puhl, H., & Rotheneder, M. (1989). Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radical Research Communications, 6, 67–75.
Noble, R. P. (1968). Electrophoretic separation of plasma lipoproteins in agarose gel. Journal of Lipid Research, 9, 693–700.
Park, K. H., Shin, D. G., Kim, J. R., & Cho, K. H. (2010). Senescence-related truncation and multimerization of apolipoprotein A-I in high-density lipoprotein with an elevated level of advanced glycated end products and cholesteryl ester transfer activity. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 65, 600–610.
Park, K. H., & Cho, K. H. (2011). High-density lipoprotein (HDL) from elderly and reconstituted HDL containing glycated apolipoproteins A-I share proatherosclerotic and prosenescent properties with increased cholesterol influx. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 66, 511–520.
Owusu-Ansah, E., Yavari, A., Mandal, S., & Banerjee, U. (2008). Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nature Genetics, 40, 356–361.
Nusslein-Volhard, C., & Dahm, R. (2002). Zebrafish: A practical approach. New York: Oxford University Press.
Park, K. H., & Cho, K. H. (2011). A zebrafish model for the rapid evaluation of pro-oxidative and inflammatory death by lipopolysaccharide, oxidized low-density lipoproteins, and glycated high-density lipoproteins. Fish & Shellfish Immunology, 31, 904–910.
Cho, K. H. (2009). Biomedicinal implications of high-density lipoprotein: Its composition, structure, functions, and clinical applications. BMB Rep., 42, 393–400.
Cho, K. H., Shin, D. G., Baek, S. H., & Kim, J. R. (2009). Myocardial infarction patients showed altered lipoprotein properties and functions when compared with stable angina pectoris patients. Experimental & Molecular Medicine, 41, 67–76.
Brown, B. E., Nobecourt, E., Zeng, J., Jenkins, A. J., Rye, K. A., & Davies, M. J. (2013). Apolipoprotein A-I glycation by glucose and reactive aldehydes alters phospholipid affinity but not cholesterol export from lipid-laden macrophages. PLoS ONE, 31, e65430.
Kim, J., Park, H. H., Choi, I., Kim, Y. O., & Cho, K. H. (2010). Severely modified lipoprotein properties without a change in cholesteryl ester transfer protein activity in patients with acute renal failure secondary to Hantaan virus infection. BMB Reports, 43, 535–540.
Johnson, R. J., Segal, M. S., Sautin, Y., Nakagawa, T., Feig, D. I., Kang, D. H., et al. (2007). Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. American Journal of Clinical Nutrition, 86, 899–906.
Hu, F. B., & Malik, V. S. (2010). Sugar-sweetened beverages and risk of obesity and type 2 diabetes: Epidemiologic evidence. Physiology & Behavior, 100, 47–54.
Gurney, J. G., Pogoda, J. M., Holly, E. A., Hecht, S. S., & Preston-Martin, S. (1997). Aspartame consumption in relation to childhood brain tumor risk: Results from a case–control study. Journal of the National Cancer Institute, 89, 1072–1074.
Soffritti, M., Belpoggi, F., Esposti, D. D., & Lambertini, L. (2005). Aspartame induces lymphomas and leukaemias in rats. European Journal of Oncology, 10, 107–116.
Lim, U., Subar, A. F., Mouw, T., Hartge, P., Morton, L. M., Stolzenberg-Solomon, R., et al. (2006). Consumption of aspartame-containing beverages and incidence of hematopoietic and brain malignancies. Cancer Epidemiology, Biomarkers & Prevention, 15, 1654–1659.
Eshak, E. S., Iso, H., Kokubo, Y., Saito, I., Yamagishi, K., Inoue, M., et al. (2012). Soft drink intake in relation to incident ischemic heart disease, stroke, and stroke subtypes in Japanese men and women: The Japan Public Health Centre-based study cohort I. American Journal of Clinical Nutrition, 96, 1390–1397.
Burkhart, C. G. (2009). ‘Lone’ atrial fibrillation precipitated by monosodium glutamate and aspartame. International Journal of Cardiology, 137, 307–308.
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This work was supported by the 2014 Yeungnam University Research Grant.
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Jae-Yong Kim and Ki-Hoon Park are co-first authors.
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Kim, JY., Park, KH., Kim, J. et al. Modified High-Density Lipoproteins by Artificial Sweetener, Aspartame, and Saccharin, Showed Loss of Anti-atherosclerotic Activity and Toxicity in Zebrafish. Cardiovasc Toxicol 15, 79–89 (2015). https://doi.org/10.1007/s12012-014-9273-z
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DOI: https://doi.org/10.1007/s12012-014-9273-z