Your browser doesn't support javascript.
loading
Dichloroacetate reactivates pyruvate-supported peroxide removal by liver mitochondria and prevents NAFLD aggravation in NAD(P)+ transhydrogenase-null mice consuming a high-fat diet.
Navarro, Claudia D C; Francisco, Annelise; Figueira, Tiago R; Ronchi, Juliana A; Oliveira, Helena C F; Vercesi, Anibal E; Castilho, Roger F.
Afiliação
  • Navarro CDC; Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, 13083-888, Brazil. Electronic address: claudia.doutunicamp@gmail.com.
  • Francisco A; Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, 13083-888, Brazil.
  • Figueira TR; Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, 13083-888, Brazil; School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, 14040-907, Brazil.
  • Ronchi JA; Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, 13083-888, Brazil.
  • Oliveira HCF; Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, 13083-862, Brazil.
  • Vercesi AE; Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, 13083-888, Brazil.
  • Castilho RF; Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, 13083-888, Brazil. Electronic address: rogerc@unicamp.br.
Eur J Pharmacol ; 917: 174750, 2022 Feb 15.
Article em En | MEDLINE | ID: mdl-35032488
The mechanisms by which a high-fat diet (HFD) promotes non-alcoholic fatty liver disease (NAFLD) appear to involve liver mitochondrial dysfunction and redox imbalance. The functional loss of the enzyme NAD(P)+ transhydrogenase, a main source of mitochondrial NADPH, results in impaired mitochondrial peroxide removal, pyruvate dehydrogenase inhibition by phosphorylation, and progression of NAFLD in HFD-fed mice. The present study aimed to investigate whether pharmacological reactivation of pyruvate dehydrogenase by dichloroacetate attenuates the mitochondrial redox dysfunction and the development of NAFLD in NAD(P)+ transhydrogenase-null (Nnt-/-) mice fed an HFD (60% of total calories from fat). For this purpose, Nnt-/- mice and their congenic controls (Nnt+/+) were fed chow or an HFD for 20 weeks and received sodium dichloroacetate or NaCl in the final 12 weeks via drinking water. The results showed that HFD reduced the ability of isolated liver mitochondria from Nnt-/- mice to remove peroxide, which was prevented by the dichloroacetate treatment. HFD-fed mice of both Nnt genotypes exhibited increased body and liver mass, as well as a higher content of hepatic triglycerides, but dichloroacetate treatment attenuated these abnormalities only in Nnt-/- mice. Notably, dichloroacetate treatment decreased liver pyruvate dehydrogenase phosphorylation levels and prevented the aggravation of NAFLD in HFD-fed Nnt-/- mice. Conversely, dichloroacetate treatment elicited moderate hepatocyte ballooning in chow-fed mice, suggesting potentially toxic effects. We conclude that the protection against HFD-induced NAFLD by dichloroacetate is associated with its role in reactivating pyruvate dehydrogenase and reestablishing the pyruvate-supported liver mitochondrial capacity to handle peroxide in Nnt-/- mice.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hepatopatia Gordurosa não Alcoólica Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hepatopatia Gordurosa não Alcoólica Idioma: En Revista: Eur J Pharmacol Ano de publicação: 2022 Tipo de documento: Article