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| Author(s): |
Joseane Morari
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2009-02-19 |
| Examining board members: |
Licio Augusto Velloso;
Claudia Pinto Marques Souza de Oliveira;
Fernando Ganzarolli de Oliveira
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| Advisor: | Licio Augusto Velloso |
| Abstract | |
Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-induced steatosis. Reducing IL-10 expression increases pro-inflammatory activity in the steatotic liver and worsens insulin resistance. Because in diet-induced steatosis the transcriptional co-activator PGC-1a plays a central role in the dysfunctional hepatocytic activity, we hypothesized that at least part of PGC-1a activity could be mediated by its effect on the transcriptional control of IL-10 expression. Here, we used immunoblot, real-time PCR, immunocytochemistry and ChIP assay to investigate the role of PGC-1a 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-1a are increased. Inhibiting PGC-1a expression by antisense oligonucleotide increases IL-10 expression and reduces the steatotic phenotype. In cultured hepatocytes the treatment with saturated and unsaturated fatty acids, increase IL-10 expression. This is accompanied by increased association of PGC-1a with c-Maf and p50-NF?B, two transcription factors known to modulate IL-10 expression. In addition, following fatty acid treatment PGC-1a, c-Maf and p50- NF?B migrate from the cytosol to the nuclei of hepatocytes and bind to the IL-10 promoter region. Inhibiting NF?B activation with salicylate reduces IL-10 expression and PGC-1a association with p50-NF?B. Thus, PGC-1a emerges as a potential transcriptional regulator of the inflammatory phenomenon taking place in the steatotic liver. (AU) | |