In the present study, we aimed to decipher the mechanisms involved in the transcriptional effect of insulin on the SREBP-1c specific promoter of the human srebf-1 gene. Using luciferase reporter gene constructs in HEK-293 cells (human embryonic kidney cells), we demonstrated that the full effect of insulin requires the presence of SREs (sterol response elements) in the proximal region of the promoter. Furthermore, insulin increases the binding of SREBP-1 (sterol-regulatory-element-binding protein-1) to this promoter region in chromatin immunoprecipitation assay. We also found that the nuclear receptors LXRs (liver X receptors) strongly activate SREBP-1c gene expression and identified the LXRE (LXR-response element) involved in this effect. However, our results suggested that these LXREs do not play a major role in the response to insulin. Finally, using expression vectors and adenoviruses allowing ectopic overexpressions of the human mature forms of SREBP-1a or SREBP-1c, we demonstrated the direct role of SREBP-1 in the control of SREBP-1c gene expression in human skeletal-muscle cells. Altogether, these results strongly suggest that the SREBP-1 transcription factors are the main mediators of insulin action on SREBP-1c expression in human tissues.