ichloroacetate reactivates pyruvate-supported peroxide removal by liver mitochondria and prevents NAFLD aggravation in NAD(P)(+) transhydrogenase-null mice consuming a high-fat die

Author(s)

Navarro, Claudia D. C. ^[1] ; Francisco, Annelise ^[1] ; Figueira, Tiago R. ^{[2, 1]} ; Ronchi, Juliana A. ^[1] ; Oliveira, Helena C. F. ^[3] ; Vercesi, Anibal E. ^[1] ; Castilho, Roger F. ^[1]

Affiliation

^[1] Univ Estadual Campinas, Fac Med Sci, Dept Pathol, UNICAMP, Rua Vital Brasil 80, BR-13083888 Campinas, SP - Brazil

^[2] Univ Sao Paulo, Sch Phys Educ & Sport Ribeirao Preto, BR-14040907 Ribeirao Preto, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Dept Struct & Funct Biol, Inst Biol, BR-13083862 Campinas, SP - Brazil

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 917, FEB 15 2022.
• Web of Science Citations: 0

Abstract

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)(+) transhydrogenasenull (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 chowfed 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. (AU)

• FAPESP's process: 20/05202-4 - The role of mitochondrial NAD(P)+ transhydrogenase in monoaminergic neurotransmission and neurodegeneration in mice
• Grantee: Annelise Francisco
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/20855-7 - The role of mitochondrial NAD(P)-Transhydrogenase in the development of Fatty Liver Disease and aging in mice
• Grantee: Claudia Daniele Carvalho Navarro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants