| dc.description.abstract | This thesis evaluated the effects of chronic administration of aspartame (ASP), as well as investigated
the effects of ASP, orlistat, and their association in the liver of healthy mice and mice with metabolicassociated fatty liver disease (MAFLD). For this, two experiments were carried out. In experiment I,
Swiss mice received 0.9% NaCl or ASP (80 mg/kg) for 12 weeks. In this experiment, oxidative and
inflammatory parameters associated with fibrosis progression were evaluated. The results showed that
the administration of ASP led to liver damage and increased aminotransferase activities. ASP also
caused liver fibrosis, evidenced by histological analysis and upregulation of pro-fibrotic factors (Tgfb1,
Col1a1, and Acta2). In addition, it caused a decrease in the activation of nuclear erythroid factor 2-
related factor 2 (Nrf2), thus decreasing the activity of antioxidant enzymes, and causing an increase in
lipid peroxidation, which probably triggered the activation of the NLRP3 inflammasome and the induction
of p53. ASP also caused a decrease in the coactivator 1α of peroxisome proliferator-activated receptor
gamma (PGC-1α) levels, possibly by the p53 activation. Moreover, it induced a worsening in the lipid
profile, accumulation of lipids in the liver, and the impairment of gluconeogenesis, evidenced by the
downregulation of its enzymes, and consequent hypoglycemia. Experiment II consisted of a period of
MAFLD induction (8 weeks) in C57BL/6 mice through a Western-type diet (WD), followed by a period of
treatment with ASP (80 mg/kg) and/or orlistat (100 mg/kg of diet) (6 weeks), totaling 14 weeks of
experiment. Biochemical, histological, oxidative stress, and glutathione (GSH) metabolism parameters
were analyzed. It was observed that WD led to an increase in body weight and adiposity, as well as
hyperglycemia, hypercholesterolemia, hepatic steatosis, increased activity of aminotransferases, and
accumulation of lipids in the liver. In addition, it caused an increase in lipid peroxidation and hydrogen
peroxide levels and a decrease in antioxidant defenses. Consumption of ASP by healthy subjects or
those with MAFLD resulted in hyperglycemia, GSH system impairment, and liver damage. In mice with
MAFLD treated with orlistat, an improvement in body weight, adiposity, liver function, oxidative
parameters, and antioxidant defenses was observed, while healthy animals showed hyperglycemia,
hypertriglyceridemia, and increased aspartate aminotransferase activity. The association of ASP and
orlistat in healthy mice led to weight loss and a decrease in adiposity, but also caused hyperglycemia,
hypercholesterolemia, and increased activity of alanine aminotransferase. In contrast, in mice with
MAFLD there was a decrease in body weight, adiposity, and in fasting glucose, as well as a reduction
of oxidative stress biomarkers, improvement of hepatic function and an increase in the antioxidant
defenses. In conclusion, ASP has toxicity when ingested by healthy individuals, but when associated
with orlistat and consumed by individuals with MAFLD, it seems beneficial. However, it is necessary to
continue the studies started in this thesis in order to better understand the mechanisms involved in the
observed effects. | |
