Functional Interaction between Sterol Regulatory Element-binding Protein-1c, Nuclear Factor Y, and 3,5,3′-Triiodothyronine Nuclear Receptors

Sterol regulatory element binding protein-1c (SREBP-1c) is a key hepatic transcription factor involved in lipogenic gene expression. In an effort to understand the role SREBP-1c plays in lipogenic gene transcription, we have examined the functional interaction between SREBP-1c, nuclear factor Y, 3,5,3'-triiodothyronine (T(3)) receptors, and co-activators using the S14 gene promoter as a model. T(3), glucose, and insulin rapidly induce S14 gene transcription in rat liver and in primary hepatocytes. Linker scanning analyses of the S14 promoter showed that an SRE at -139/-131 base pairs (bp) binding SREBP-1c and a Y-box at -104/-99 bp binding NF-Y are indispensable for both T(3)- and SREBP-1c-mediated induction of S14 promoter activity in rat primary hepatocytes. T(3) and glucose/insulin induce S14 gene transcription through separate enhancers. Enhancer substitution studies reveal a preferential interaction between SREBP-1c.NF-Y and the T(3) regulatory region (-2.8/-2.5 kb) binding thyroid hormone receptor/RXR heterodimers. Elevating hepatocellular levels of specific co-activators (CBP, p/CAF, or GCN5) induced S14 promoter activity 2-3-fold, while SREBP-1c induced promoter activity 10-fold. The combination of these treatments induced S14 promoter activity (20-35-fold). However, this additive effect was lost when the T(3) regulatory region was deleted. Based on these results, we suggest that the SREBP-1c.NF-Y complex facilitates the interaction between co-activators that are recruited to distal hormone-regulated enhancers and the general transcription machinery that binds the S14 proximal promoter.