Stra13/DEC1 and DEC2 inhibit sterol regulatory element binding protein-1c in a hypoxia-inducible factor-dependent mechanism

Sterol regulatory element binding protein-1c (SREBP-1c) is a basic helix-loop-helix (bHLH) homodimeric transactivator, which induces itself and several lipogenic enzymes, notably fatty acid synthase (FAS). We demonstrated that hypoxia-inducible factor (HIF) represses the SREBP-1c gene by inducing Stimulated with retinoic acid (Stra)13/Differentiated embryo chondrocyte 1(DEC1) and its isoform, DEC2. Stra13/DEC1 and DEC2 are bHLH homodimeric transcription repressors. We found that both Stra13 and DEC2 inhibit SREBP-1c-induced transcription by competing with SREBP-1c for binding to the E-box in the SREBP-1c promoter and/or by interacting with SREBP-1c protein. DEC2 is instantly and temporarily induced in acute hypoxia, while Stra13 is induced in prolonged hypoxia. This expression profile reflects the finding that Stra13 represses DEC2, thus maintains low level of DEC2 in prolonged hypoxia. DEC2-siRNA restores the hypoxic repression but Stra13-siRNA fails to do so, suggesting that DEC2 is the major initiator of hypoxic repression of SREBP-1c, whereas Stra13 substitutes for DEC2 in prolonged hypoxia. Our findings imply that Stra13 and DEC2 are the mediators to repress SREBP-1c gene in response to hypoxia. By doing so, HIF and its targets, Stra13 and DEC2 reduce the ATP consuming anabolic lipogenesis prior to the actual decrease of ATP acting as a feed-forward mechanism.