C/EBP transcription factors regulate SREBP1c gene expression during adipogenesis

The transcription factor SREBP1c (sterol-regulatory-element-binding protein 1c) is highly expressed in adipose tissue and plays a central role in several aspects of adipocyte development including the induction of PPAR gamma (peroxisome-proliferator-activated receptor gamma), the generation of an endogenous PPAR gamma ligand and the expression of several genes critical for lipid biosynthesis. Despite its significance, the regulation of SREBP1c expression during adipogenesis is not well characterized. We have noted that in several models of adipogenesis, SREBP1c expression closely mimics that of known C/EBP beta (CCAAT/enhancer-binding protein beta) targets. Inhibition of C/EBP activity during adipogenesis by expressing either the dominant-negative C/EBP beta LIP (liver-enriched inhibitory protein) isoform, the co-repressor ETO (eight-twenty one/MTG8) or using siRNAs (small interfering RNAs) targeting either C/EBP beta or C/EBP delta significantly impaired early SREBP1c induction. Furthermore, ChIP (chromatin immunoprecipitation) assays identified specific sequences in the SREBP1c promoter to which C/EBP beta and C/EBP delta bind in intact cells, demonstrating that these factors may directly regulate SREBP1c expression. Using cells in which C/EBP alpha expression is inhibited using shRNA (short hairpin RNA) and ChIP assays we show that C/EBP alpha replaces C/EBP beta and C/EBP delta as a regulator of SREBP1c expression in maturing adipocytes. These results provide novel insight into the induction of SREBP1c expression during adipogenesis. Moreover, the findings of the present study identify an important additional mechanism via which the C/EBP transcription factors may control a network of gene expression regulating adipogenesis, lipogenesis and insulin sensitivity.