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High-fat diet inhibits PGC-1α suppressive effect on NFκB signaling in hepatocytes

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Abstract

Purpose

The peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) regulates the expression of genes implicated in fatty acid oxidation and oxidative phosphorylation. Its role in liver steatosis is well established, since mice with liver-specific deletion of PGC-1α exhibit lipid accumulation and high-fat diet reduces hepatic PGC-1α expression in mice. In this study, we investigated the role of PGC-1α in the inflammatory changes observed in steatohepatitis induced by high-fat diet.

Methods

C57black/6 mice were fed a high-fat diet containing 30% fat for 10 weeks. After euthanasia, liver morphology was examined by HE staining and inflammation was determined by IL-6, TNF-α, and IL-1β quantification. Liver gene expression of PGC-1 isoforms was evaluated by real-time PCR and p65 NFκB nuclear translocation by Western blotting. HepG2 cells were treated with linoleic acid overload for 72 h to create an in vitro model of steatohepatitis. RNA interference (RNAi) was used to evaluate the involvement of PGC-1α on inflammatory mediators’ production by hepatocytes.

Results

The high-fat diet led to a state of nonalcoholic steatohepatitis, associated with increased deposits of intra-abdominal fat, hyperglycemia and hyperlipidemia. Mice liver also exhibited increased proinflammatory cytokines’ levels, decreased PGC-1α expression, and marked increase in p65 NFκB nuclear translocation. Linoleic acid treated cells also presented increased expression of proinflammatory cytokines and decreased PGC-1α expression. The knockdown of PGC-1α content caused an increase in IL-6 expression and release via enhanced IκBα phosphorylation and subsequent increase of p65 NFκB nuclear translocation.

Conclusion

High-fat diet induces liver inflammation by inhibiting PGC-1α expression and its suppressive effect in NFκB pathway.

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Author information

Authors and Affiliations

  1. Department of Clinical Medicine, Medical School, Emergency Medicine Laboratory (LIM51), University of São Paulo, Av. Dr. Arnaldo, 455, São Paulo, SP, 01246-903, Brazil

    Wermerson Assunção Barroso, Vanessa Jacob Victorino, Isabela Casagrande Jeremias, Ricardo Costa Petroni, Suely Kunimi Kubo Ariga, Denise Frediani Barbeiro, Thais Martins de Lima & Heraldo Possolo de Souza

  2. Heart Institute (InCor), University of Sao Paulo Medical School, São Paulo, Brazil

    Thiago A Salles

Authors
  1. Wermerson Assunção Barroso
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  2. Vanessa Jacob Victorino
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  3. Isabela Casagrande Jeremias
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  4. Ricardo Costa Petroni
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  5. Suely Kunimi Kubo Ariga
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  6. Thiago A Salles
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  7. Denise Frediani Barbeiro
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  8. Thais Martins de Lima
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  9. Heraldo Possolo de Souza
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Contributions

Design and conduct of the study: WAB, TAS, TML, HPS. Data collection and analysis: WAB, VJV, ICJ, RCP, SKA, DFB. Data interpretation: WAB, TAS, TML, HPS. Manuscript writing: WAB, TAS, TML, HPS.

Corresponding author

Correspondence to Thais Martins de Lima.

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Funding

This work was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2012/07957-6).

Conflict of interest

No conflicts of interest, financial or otherwise, are declared by the author(s).

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Barroso, W.A., Victorino, V.J., Jeremias, I.C. et al. High-fat diet inhibits PGC-1α suppressive effect on NFκB signaling in hepatocytes. Eur J Nutr 57, 1891–1900 (2018). https://doi.org/10.1007/s00394-017-1472-5

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  • DOI: https://doi.org/10.1007/s00394-017-1472-5

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