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.