The role of transcription coactivators PGC-1 in the inflammatory process
| Full text | |
| Author(s): |
Navarro, Claudia D. C.
[1]
;
Figueira, Tiago R.
[1]
;
Francisco, Annelise
[1]
;
Dal'Bo, Genoefa A.
[1]
;
Ronchi, Juliana A.
[1]
;
Rovani, Juliana C.
[2]
;
Escanhoela, Cecilia A. F.
[3]
;
Oliveira, Helena C. F.
[2]
;
Castilho, Roger F.
[1]
;
Vercesi, Anibal E.
[1]
Total Authors: 10
|
| Affiliation: | [1] Univ Estadual Campinas UNICAMP, Fac Ciencias Med, Dept Patol Clin, BR-13083887 Campinas, SP - Brazil
[2] Univ Estadual Campinas UNICAMP, Inst Biol, Dept Biol Estrut & Func, BR-13083865 Campinas, SP - Brazil
[3] Univ Estadual Campinas UNICAMP, Fac Ciencias Med, Dept Anat Patol, BR-13083887 Campinas, SP - Brazil
Total Affiliations: 3
|
| Document type: | Journal article |
| Source: | Free Radical Biology and Medicine; v. 113, p. 190-202, DEC 2017. |
| Web of Science Citations: | 9 |
| Abstract | |
The mechanisms by which a high fat diet (HFD) promotes non-alcoholic fatty liver disease (NAFLD) appear to involve liver mitochondrial dysfunctions and redox imbalance. We hypothesized that a HFD would increase mitochondrial reliance on NAD(P)-transhydrogenase (NNT) as the source of NADPH for antioxidant systems that counteract NAFLD development. Therefore, we studied HFD-induced liver mitochondrial dysfunctions and NAFLD in C57Unib. B6 congenic mice with (Nnt(+/+)) or without (Nnt(-/-)) NNT activity; the spontaneously mutated allele (Nnt(-/-)) was inherited from the C57BL/6J mouse substrain. After 20 weeks on a HFD, Nnt(-/-) mice exhibited a higher prevalence of steatohepatitis and content of liver triglycerides compared to Nnt(+/+) mice on an identical diet. Under a HFD, the aggravated NAFLD phenotype in the Nnt(-/-) mice was accompanied by an increased H2O2 release rate from mitochondria, decreased aconitase activity (a redox-sensitive mitochondrial enzyme) and higher susceptibility to Ca2+ -induced mitochondrial permeability transition. In addition, HFD led to the phosphorylation (inhibition) of pyruvate dehydrogenase (PDH) and markedly reduced the ability of liver mitochondria to remove peroxide in Nnt(-/-) mice. Bypass or pharmacological reactivation of PDH by dichloroacetate restored the peroxide removal capability of mitochondria from Nnt-/-mice on a HFD. Noteworthy, compared to mice that were chow-fed, the HFD did not impair peroxide removal nor elicit redox imbalance in mitochondria from Nnt(+/+) mice. Therefore, HFD interacted with Nnt mutation to generate PDH inhibition and further suppression of peroxide removal. We conclude that NNT plays a critical role in counteracting mitochondrial redox imbalance, PDH inhibition and advancement of NAFLD in mice fed a HFD. The present study provide seminal experimental evidence that redox imbalance in liver mitochondria potentiates the progression from simple steatosis to steatohepatitis following a HFD. (AU) | |
| FAPESP's process: | 13/07607-8 - OCRC - Obesity and Comorbidities Research Center |
| Grantee: | Licio Augusto Velloso |
| Support type: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |
| FAPESP's process: | 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders |
| Grantee: | Aníbal Eugênio Vercesi |
| Support type: | Research Projects - Thematic Grants |
| FAPESP's process: | 15/22063-0 - Antioxidant role of the nicotinamide nucleotide transhydrogenase (NNT) in the central nervous system - morphofunctional characterization in control mice and spontaneously NNT gene mutant mice |
| Grantee: | Annelise Francisco |
| Support type: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 14/02819-0 - Investigation of glucose and lipid metabolism alterations in a model of nicotinamide nucleotide transhydrogenase mitochondrial (NNT)deficiency |
| Grantee: | Juliana Cristine Rovani Rodrigues |
| Support type: | Scholarships in Brazil - Doctorate |