Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos

Detalhes bibliográficos
Autor(a) principal: Bressan, Caroline Azzolin
Data de Publicação: 2023
Tipo de documento: Tese
Idioma: por
Título da fonte: Manancial - Repositório Digital da UFSM
Texto Completo: http://repositorio.ufsm.br/handle/1/28323
Resumo: 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.
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spelling Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativosEffects of aspartame and orlistat in healthy animals and animals with metabolic-associated fatty liver disease: biochemical, metabolic and oxidative parametersEsteatoseFibroseAdoçantesEstresse oxidativoFarmacoterapia antiobesidadeSteatosisFibrosisSweetenersOxidative stressAntiobesity pharmacotherapyCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAThis 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.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESEsta tese avaliou os efeitos da administração crônica de aspartame (ASP), assim como investigou os efeitos do ASP, do orlistate e de sua associação em fígado de camundongos saudáveis e com doença gordurosa do fígado associada a disfunção metabólica (MAFLD). Para isto, foram realizados dois experimentos. No experimento I, camundongos Swiss receberam NaCl 0,9% ou ASP (80 mg/kg) durante 12 semanas. Neste experimento foram avaliados parâmetros oxidativos e inflamatórios associados com a progressão da fibrose. Os resultados obtidos demonstraram que a administração de ASP levou ao dano hepático e aumentou a atividade das aminotransferases. O ASP também causou fibrose hepática, evidenciada por análise histológica e elevação da expressão gênica de fatores prófibróticos (Tgfb1, Col1a1 e Acta2). Além disso, causou a diminuição da ativação do fator nuclear eritroide 2 relacionado ao fator 2 (Nrf2), diminuindo assim a atividade de enzimas antioxidantes, e causando o aumento da lipoperoxidação, o que provavelmente desencadeou a ativação do inflamassoma NLRP3 e a indução da p53. O ASP também levou a redução dos níveis do coativador do receptor ativado por proliferadores de peroxissoma gama 1α (PGC-1α), possivelmente pela ativação da p53. Observou-se uma piora no perfil lipídico, o acúmulo de lipídeos no fígado e o prejuízo na gliconeogênese, evidenciada pela diminuição da expressão gênica das enzimas desta via, e consequente hipoglicemia. O experimento II, consistiu em um período de indução da MAFLD (8 semanas) em camundongos C57BL/6 através de uma dieta tipo ocidental (WD), seguido por um período de tratamento com ASP (80 mg/kg) e/ou orlistate (100 mg/kg de dieta) (6 semanas), totalizando 14 semanas de experimento. Foram analisados parâmetros bioquímicos, histológicos, do metabolismo da glutationa (GSH) e de estresse oxidativo. Com os resultados verificou-se que a WD levou ao aumento do peso corporal e adiposidade, assim como hiperglicemia, hipercolesterolemia, esteatose hepática, aumento da atividade das aminotransferases e acúmulo de lipídeos no fígado. Além disso, causou aumento da lipoperoxidação e dos níveis de peróxido de hidrogênio e diminuição das defesas antioxidantes. O consumo de ASP por indivíduos saudáveis ou com MAFLD resultou em hiperglicemia, prejuízo do sistema da GSH e dano hepático. Em camundongos com MAFLD tratados com orlistate observou-se uma melhora no peso corporal, adiposidade, função hepática, parâmetros oxidativos e defesa antioxidante, enquanto os animais saudáveis apresentaram hiperglicemia, hipertrigliceridemia e aumento da atividade da aspartato aminotransferase. A associação de ASP e orlistate em camundongos saudáveis levou a perda de peso e a diminuição da adiposidade, mas também causou hiperglicemia, hipercolesterolemia e aumento da atividade da alanina aminotransferase, enquanto em camundongos com MAFLD verificou-se a diminuição do peso corporal, da adiposidade e da glicemia, assim como a redução dos biomarcadores de estresse oxidativo e a melhora da função hepática e o aumento das defesas antioxidantes. Conclui-se que o aspartame possui toxicidade quando ingerido por indivíduos saudáveis, porém quando associado com orlistate e consumido por indivíduos com MAFLD, parece ser benéfico. No entanto, se faz necessário dar continuidade aos estudos iniciados nesta tese para que se possa melhor compreender os mecanismos por trás dos efeitos observados.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em FarmacologiaCentro de Ciências da SaúdePavanato, Maria Amáliahttp://lattes.cnpq.br/8701892865724171Finamor, Isabela AndresMarron, Norma Anair PossaPartata, Wânia AparecidaRichards, Neila Silvia Pereira dos SantosBrucker, NatáliaBressan, Caroline Azzolin2023-03-22T13:13:45Z2023-03-22T13:13:45Z2023-01-18info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/28323porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2023-03-22T13:13:45Zoai:repositorio.ufsm.br:1/28323Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2023-03-22T13:13:45Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false
dc.title.none.fl_str_mv Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
Effects of aspartame and orlistat in healthy animals and animals with metabolic-associated fatty liver disease: biochemical, metabolic and oxidative parameters
title Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
spellingShingle Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
Bressan, Caroline Azzolin
Esteatose
Fibrose
Adoçantes
Estresse oxidativo
Farmacoterapia antiobesidade
Steatosis
Fibrosis
Sweeteners
Oxidative stress
Antiobesity pharmacotherapy
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
title_short Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
title_full Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
title_fullStr Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
title_full_unstemmed Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
title_sort Efeitos do aspartame e do orlistate em animais saudáveis e com doença gordurosa do fígado associada a disfunção metabólica: parâmetros bioquímicos, metabólicos e oxidativos
author Bressan, Caroline Azzolin
author_facet Bressan, Caroline Azzolin
author_role author
dc.contributor.none.fl_str_mv Pavanato, Maria Amália
http://lattes.cnpq.br/8701892865724171
Finamor, Isabela Andres
Marron, Norma Anair Possa
Partata, Wânia Aparecida
Richards, Neila Silvia Pereira dos Santos
Brucker, Natália
dc.contributor.author.fl_str_mv Bressan, Caroline Azzolin
dc.subject.por.fl_str_mv Esteatose
Fibrose
Adoçantes
Estresse oxidativo
Farmacoterapia antiobesidade
Steatosis
Fibrosis
Sweeteners
Oxidative stress
Antiobesity pharmacotherapy
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
topic Esteatose
Fibrose
Adoçantes
Estresse oxidativo
Farmacoterapia antiobesidade
Steatosis
Fibrosis
Sweeteners
Oxidative stress
Antiobesity pharmacotherapy
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023-03-22T13:13:45Z
2023-03-22T13:13:45Z
2023-01-18
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://repositorio.ufsm.br/handle/1/28323
url http://repositorio.ufsm.br/handle/1/28323
dc.language.iso.fl_str_mv por
language por
dc.rights.driver.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidade Federal de Santa Maria
Brasil
Farmacologia
UFSM
Programa de Pós-Graduação em Farmacologia
Centro de Ciências da Saúde
publisher.none.fl_str_mv Universidade Federal de Santa Maria
Brasil
Farmacologia
UFSM
Programa de Pós-Graduação em Farmacologia
Centro de Ciências da Saúde
dc.source.none.fl_str_mv reponame:Manancial - Repositório Digital da UFSM
instname:Universidade Federal de Santa Maria (UFSM)
instacron:UFSM
instname_str Universidade Federal de Santa Maria (UFSM)
instacron_str UFSM
institution UFSM
reponame_str Manancial - Repositório Digital da UFSM
collection Manancial - Repositório Digital da UFSM
repository.name.fl_str_mv Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)
repository.mail.fl_str_mv atendimento.sib@ufsm.br||tedebc@gmail.com
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