The role of proliferator-activated receptor γ coactivator–1 α in the fatty-acid–dependent transcriptional control of interleukin-10 in hepatic cells of rodents

• Published in: Metabolism, clinical and experimental clinical and experimental, 2010-02, Vol.59 (2), p.215-223
• Main Authors: Morari, Joseane, Torsoni, Adriana S, Anhê, Gabriel F, Roman, Erika A, Cintra, Dennys E, Ward, Laura S, Bordin, Silvana, Velloso, Lício A
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Endocrinology & Metabolism; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2009.07.020

Abstract Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-induced steatosis. Reducing IL-10 expression increases proinflammatory activity in the steatotic liver and worsens insulin resistance. As the transcriptional coactivator proliferator-activated receptor γ coactivator–1 α (PGC-1 α ) plays a central role in dysfunctional hepatocytic activity in diet-induced steatosis, we hypothesized that at least part of the action of PGC-1 α could be mediated by reducing the transcription of the IL-10 gene. Here, we used immunoblotting, real-time polymerase chain reaction, immunocytochemistry, and chromatin immunoprecipitation assay to investigate the role of PGC-1 α in the control of IL-10 expression in hepatic cells. First, we show that, in the intact steatotic liver, the expressions of IL-10 and PGC-1 α are increased. Inhibiting PGC-1 α expression by antisense oligonucleotide increases IL-10 expression and reduces the steatotic phenotype. In cultured hepatocytes, the treatment with saturated and unsaturated fatty acids increased IL-10 expression. This was accompanied by increased association of PGC-1 α with c-Maf and p50–nuclear factor (NF) κ B, 2 transcription factors known to modulate IL-10 expression. In addition, after fatty acid treatment, PGC-1 α , c-Maf, and p50-NF κ B migrate from the cytosol to the nuclei of hepatocytes and bind to the IL-10 promoter region. Inhibiting NF κ B activation with salicylate reduces IL-10 expression and the association of PGC-1 α with p50-NF κ B. Thus, PGC-1 α emerges as a potential transcriptional regulator of the inflammatory phenomenon taking place in the steatotic liver.