Abstract
Increased accumulation and/or impaired utilization of fatty acid in extra-adipose tissues are implicated in the pathogenesis of insulin resistance and type 2 diabetes. Pyruvate dehydrogenase kinase 4 (Pdk4) is a key enzyme involved in fatty oxidation and energy expenditure, and its expression can be repressed by pro-inflammatory stimuli. Previously, we have shown that class II transactivator (CIITA) mediates the adverse effect of interferon gamma (IFN-γ) in skeletal muscle cells by cooperating with hypermethylated in cancer 1 (HIC1) to repress silent information regulator 1 (SIRT1) transcription. Building upon this finding, we report here that CIITA interacted with HIC1 via the GTP-binding domain (GBD) while HIC1 interacted with CIITA via the BTB/POZ domain. The GBD domain was required for CIITA to repress SIRT1 transcription probably acting as a bridge for CIITA to bind to HIC1 and consequently to bind to the SIRT1 promoter. IFN-γ stimulation, CIITA over-expression, or HIC1 over-expression repressed Pdk4 promoter activity while silencing either CIITA or HIC1 normalized Pdk4 expression in the presence of IFN-γ. An increase in SIRT1 expression or activity partially rescued Pdk4 expression in the presence of CIITA, but SIRT1 inhibition abrogated Pdk4 normalization even in the absence of CIITA. Taken together, our data have identified a HIC1-CIITA-SIRT1 axis that regulates Pdk4 transcription in response to IFN-γ stimulation.
Highlights
Changes in lifestyle have contributed to the development of metabolic syndrome in humans over the past several decades[1]
We have addressed several lingering issues: 1) which domains within class II transactivator (CIITA) and hypermethylated in cancer 1 (HIC1) mediate their interaction? 2) Do CIITA and HIC1 mediate the repression of Pyruvate dehydrogenase kinase 4 (Pdk4), a key enzyme involved in fatty acid oxidation, by IFN-c? 3) Is silent information regulator 1 (SIRT1) required for CIITA to mediate the disruptive effect of IFN-c? Our data re-affirm the HIC1-CIITA-SIRT1 axis in regulating cellular metabolism in skeletal muscle cells
We have found that CIITA mediated SIRT1 repression as a result of IFN-c stimulation by interacting with HIC1
Summary
Changes in lifestyle have contributed to the development of metabolic syndrome in humans over the past several decades[1]. Type 2 diabetes, which has become a global pandemic, is a major form of metabolic syndrome[2]. Type 2 diabetes is characterized by insulin resistance in peripheral organs including the liver, adipose tissues, and skeletal muscles. Low-magnitude inflammation (dubbed as metabolic inflammation) has been extensively investigated as a primary force to promote insulin resistance[3]. (MCP1), tumor necrosis factor (TNF-c), and interferon gamma (IFN-c), are considered culprits in metabolic inflammation and insulin resistance[4,5,6]. How these proinflammatory mediators disrupt normal cellular metabolic programs and cause metabolic syndrome is not entirely clear
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