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- Title
High-fat diet inhibits PGC-1α suppressive effect on NFκB signaling in hepatocytes.
- Authors
Barroso, Wermerson Assunção; Victorino, Vanessa Jacob; Jeremias, Isabela Casagrande; Petroni, Ricardo Costa; Ariga, Suely Kunimi Kubo; Salles, Thiago A; Barbeiro, Denise Frediani; de Lima, Thais Martins; de Souza, Heraldo Possolo
- 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.
- Subjects
LIVER analysis; ANIMAL experimentation; CYTOKINES; FATTY liver; FAT content of food; HISTOLOGICAL techniques; INFLAMMATION; MICE; STAINS &; staining (Microscopy); WESTERN immunoblotting; DNA-binding proteins; NUCLEAR proteins; PEROXISOME proliferator-activated receptors; IN vitro studies; IN vivo studies
- Publication
European Journal of Nutrition, 2018, Vol 57, Issue 5, p1891
- ISSN
1436-6207
- Publication type
Article
- DOI
10.1007/s00394-017-1472-5