The role of proliferator-activated receptor gamma coactivator-1alpha in the fatty-acid-dependent transcriptional control of interleukin-10 in hepatic cells of rodents.
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 gamma coactivator-1alpha (PGC-1alpha) plays a central role in dysfunctional hepatocytic activity in diet-induced steatosis, we hypothesized that at least part of the action of PGC-1alpha 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-1alpha 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-1alpha are increased. Inhibiting PGC-1alpha 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-1alpha with c-Maf and p50-nuclear factor (NF) kappaB, 2 transcription factors known to modulate IL-10 expression. In addition, after fatty acid treatment, PGC-1alpha, c-Maf, and p50-NFkappaB migrate from the cytosol to the nuclei of hepatocytes and bind to the IL-10 promoter region. Inhibiting NFkappaB activation with salicylate reduces IL-10 expression and the association of PGC-1alpha with p50-NFkappaB. Thus, PGC-1alpha emerges as a potential transcriptional regulator of the inflammatory phenomenon taking place in the steatotic liver.
Morari
Joseane
J
Department of Internal Medicine, University of Campinas, Brazil.
Torsoni
Adriana S
AS
Anhê
Gabriel F
GF
Roman
Erika A
EA
Cintra
Dennys E
DE
Ward
Laura S
LS
Bordin
Silvana
S
Velloso
Lício A
LA
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D005234:Fatty Liver / Q000235:genetics / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000648:ultrastructure; D016753:Interleukin-10 / Q000235:genetics*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects
D005227:Fatty Acids; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D051257:Proto-Oncogene Proteins c-maf; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016753:Interleukin-10; D004247:DNA