ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose

The transcription of genes encoding proteins involved in the hepatic synthe sis of lipids from glucose is strongly stimulated by carbohydrate feeding. It is now well established that in the liver, glucose is the main activator of the expression of this group of genes, with insulin having only a permi ssive role. While ADD1/SREBP-1 has been implicated in lipogenic gene expres sion through temporal association with food intake and ectopic gain-of-func tion experiments, no genetic evidence for a requirement for this factor in glucose-mediated gene expression has been established. We show here that th e transcription of ADD1/SREBP-1c in primary cultures of hepatocytes is cont rolled positively by insulin and negatively by glucagon and cyclic AMP, est ablishing a link between this transcription factor and carbohydrate availab ility. Using adenovirus-mediated transfection of a powerful dominant negati ve form of ADD1/SREBP-1c in rat hepatocytes, we demonstrate that this facto r is absolutely necessary for the stimulation by glucose of L-pyruvate kina se, fatty acid synthase, S14, and acetyl coenzyme A carboxylase gene expres sion. These results demonstrate that ADD1/SREBP-1c plays a crucial role in mediating the expression of lipogenic genes induced by glucose and insulin.