Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Abstract

Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

Artificial Sweeteners Perturbed Liver Enzymes in Rat Model

“…after 12 weeks, liver fibrosis, elevated liver enzymes and reduced enzyme antioxidant activity was proven. 21 Many other researches [22][23][24] have highlighted and supported our results regarding the hepatotoxicity, nephrotoxicity and oxidative stress on liver caused by aspartame. Liver protection trial has been commenced against drug deleterious effects using herbal remedies, 25 propolis, 26 vitamins, 27,28 and zinc as a mineral.…”

Aspartame Consumption, Mitochondrial Disorder-Induced Impaired Ovarian Function, and Infertility Risk

“…Aspartame may induce oxidative stress through both decreased antioxidative enzyme expression and increased reactive oxygen species production, which were determined in the ovary and granulosa cells. Fimanor et al presented that malondialdehyde lipid peroxide in the liver was significantly increased and the activities of SOD-2, CAT, and glutathione peroxidase were significantly decreased, leading to an imbalance of oxidative stress after aspartame intervention for 12 weeks [ 11 ]. Similar effects were observed in the heart [ 20 ].…”

“…Despite its widespread use, the safety of aspartame remains controversial [ 8 ]. Some recent studies have implicated the consumption of aspartame as being associated with impacts on human or rat physiological responses such as glucose intolerance [ 9 ], body fat distribution [ 10 ], and liver damage [ 11 ]. Although studies have suggested the adverse effects of aspartame consumption, they were primarily based on animal experiments, and data from human studies are scant [ 12 ].…”

Clues to the Harmful Effects of Aspartame on Liver Morphology and Function

“…In addition to the aspartame-induced cellular changes in the hepatocytes, another study reported hepatic fibrosis in mice through oxidative stress due to the long-term administration of aspartame over 12 weeks at 80mg/kg/day (24). Conversely, the current study's dosage over 10 weeks of 50-250 mg/kg/day did not result in any change being found regarding the amount or distribution of collagen in any of the groups, neither through the HE staining nor with the trichrome staining.…”