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

Abstract

Long-term consumption of artificial sweeteners (AS) has been the recent focus of safety concerns. However, the potential risk of the AS in cardiovascular disease and lipoprotein metabolism has not been investigated sufficiently. We compared the influence of AS (aspartame, acesulfame K, and saccharin) and fructose in terms of functional and structural correlations of apolipoprotein (apo) A-I and high-density lipoproteins (HDL), which have atheroprotective effects. Long-term treatment of apoA-I with the sweetener at physiological concentration (3 mM for 168 h) resulted in loss of antioxidant and phospholipid binding activities with modification of secondary structure. The AS treated apoA-I exhibited proteolytic cleavage to produce 26 kDa-fragment. They showed pro-atherogenic properties in acetylated LDL phagocytosis of macrophages. Each sweetener alone or sweetener-treated apoA-I caused accelerated senescence in human dermal fibroblasts. These results suggest that long-term consumption of AS might accelerate atherosclerosis and senescence via impairment of function and structure of apoA-I and HDL.

A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients

“…Thus, we have described, for the fi rst time, the increase of a 26 kDa N-terminal truncated form of ApoA-I that we have named ApoA-I ⌬ (1-38) that associates to the denser LDL particles in DM patients which may have effects in lipoprotein particle turnover, increase LDL susceptibility to oxidation, and further contribute to a higher cardiovascular risk. The presence of cleaved ApoA-I variants is closely related to the incidence of chronic diseases such as diabetes, atherosclerosis, and ageing ( 55 ). Therefore the potential role of this truncated Supplemental Material can be found at:…”

Atherogenicity of Monosaccharides, Disaccharides and Artificial Sweeteners in the Lipid-Laden Macrophage Model System: Cell Culture and Mice Studies

“…Another study showed that treatment of apolipoproteinA-1 and HDL with 3mM of saccharin or aspartame for 16h resulted in the loss of their antioxidant and phospholipid binding activities, and accelerated the senescence of human dermal fibroblasts [29]. High artificial sweeteners intake was shown to be associated with increased BMI and body fat percentage in males and females [22,67].…”

“…In atherosclerotic apolipoprotein E-deficient (apoE-/-) mice, consumption of aspartame-acesulfame K sweetened 'light' cola was found to accelerate the progression of atherosclerotic plaques and the accumulation of sub-endothelial lipid-laden macrophages [27,28]. Also, in vitro treatment of apoA-I or HDL with physiological concentrations of aspartame, acesulfame K, or saccharin resulted in their pro-oxidative and pro-atherogenic modifications [29,30]. On the other hand, consumption of stevioside by leptin and LDLR double knockout mice was reported to reduce the aortic plaque volume by decreasing the content of macrophages, lipids, and ox-LDL in the plaque [31].…”

Modified High-Density Lipoproteins by Artificial Sweetener, Aspartame, and Saccharin, Showed Loss of Anti-atherosclerotic Activity and Toxicity in Zebrafish

“…In a previous paper, we compared the functional and structural effects of AS on apolipoprotein A-I (apoA-I), which is a major protein component of high-density lipoprotein (HDL). Among the various AS, saccharin induced the most severe impairment of apoA-I in addition to pro-senescence activity [3]. However, aspartame-fed hypercholesterolemic zebrafish display acute death with swimming defects, suggesting putative brain damage induced by aspartame [4].…”

“…We have previously reported that the properties of both apoA-I and rHDL are impaired by fructosylation [7] or AS treatment [3]. However, it remains unknown whether or not the properties of human plasma HDL are affected by treatment with fructose or AS.…”