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

• DOI: 10.1007/s00394-017-1472-5
• Publication Date: 2017-05-24T02:52:38Z
• Authors: Wermerson Assunçã...; Vanessa Jacob Vic...; Isabela Casagrand...; Ricardo Costa Pet...; Suely Kunimi Kubo...; Thiago A Salles; Denise Frediani B...; Thais Martins de ...; Heraldo Possolo d...
• Keywords: Proinflammatory cytokine; Steatosis; Steatohepatitis; Hyperlipidemia

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