RESUMO
Metabolic homeostasis is achieved through balanced energy storage and output. Impairment of energy expenditure is a hallmark event in patients with obesity and type 2 diabetes. Previously we have shown that the pro-inflammatory cytokine interferon gamma (IFN-γ) disrupts energy expenditure in skeletal muscle cells via hypermethylated in cancer 1 (HIC1)-class II transactivator (CIITA) dependent repression of SIRT1 transcription. Here we report that repression of SIRT1 transcription by IFN-γ paralleled loss of histone acetylation on the SIRT1 promoter region with simultaneous recruitment of histone deacetylase 4 (HDAC4). IFN-γ activated HDAC4 in vitro and in vivo by up-regulating its expression and stimulating its nuclear accumulation. HIC1 and CIITA recruited HDAC4 to the SIRT1 promoter and cooperated with HDAC4 to repress SIRT1 transcription. HDAC4 depletion by small interfering RNA or pharmaceutical inhibition normalized histone acetylation on the SIRT1 promoter and restored SIRT1 expression in the presence of IFN-γ. Over-expression of HDAC4 suppressed the transcription of genes involved in energy expenditure in a SIRT1-dependent manner. In contrast, HDAC4 knockdown/inhibition neutralized the effect of IFN-γ on cellular metabolism by normalizing SIRT1 expression. Therefore, our data reveal a role for HDAC4 in regulating cellular energy output and as such provide insights into rationalized design of novel anti-diabetic therapeutics.
Assuntos
Histona Desacetilases/genética , Interferon gama/genética , Proteínas Repressoras/genética , Sirtuína 1/genética , Transcrição Gênica , Acetilação , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Metabolismo Energético/genética , Regulação da Expressão Gênica , Histona Desacetilases/biossíntese , Humanos , Interferon gama/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Nucleares/genética , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regiões Promotoras Genéticas , Proteínas Repressoras/biossíntese , Sirtuína 1/biossíntese , Transativadores/genética , Ativação Transcricional/genéticaRESUMO
Chronic inflammation impairs metabolic homeostasis and is intimately correlated with the pathogenesis of type 2 diabetes. The pro-inflammatory cytokine IFN-γ is an integral part of the metabolic inflammation circuit and contributes significantly to metabolic dysfunction. The underlying mechanism, however, remains largely unknown. In the present study, we report that IFN-γ disrupts the expression of genes key to cellular metabolism and energy expenditure by repressing the expression and activity of SIRT1 at the transcription level. Further analysis reveals that IFN-γ requires class II transactivator (CIITA) to repress SIRT1 transcription. CIITA, once induced by IFN-γ, is recruited to the SIRT1 promoter by hypermethylated in cancer 1 (HIC1) and promotes down-regulation of SIRT1 transcription via active deacetylation of core histones surrounding the SIRT1 proximal promoter. Silencing CIITA or HIC1 restores SIRT1 activity and expression of metabolic genes in skeletal muscle cells challenged with IFN-γ. Therefore, our data delineate an IFN-γ/HIC1/CIITA axis that contributes to metabolic dysfunction by suppressing SIRT1 transcription in skeletal muscle cells and as such shed new light on the development of novel therapeutic strategies against type 2 diabetes.