Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes

Hepatic glucokinase plays a key role in glucose metabolism as underlined by the anomalies associated with glucokinase mutations and the consequences o f tissue-specific knock-out, In the liver, glucokinase transcription is abs olutely dependent on the presence of insulin. The cis-elements and trans-ac ting factors that mediate the insulin effect are presently unknown; this is also the case for most insulin-responsive genes. We have shown previously that the hepatic expression of the transcription factor sterol regulatory e lement binding protein-lc (SREBP-1c) is activated by insulin, We show here in primary cultures of hepatocytes that the adenovirus-mediated transductio n of a dominant negative form of SREBP-1c inhibits the insulin effect on en dogenous glucokinase expression, Conversely, in the absence of insulin, the adenovirus-mediated transduction of a dominant positive form of SREBP-1c o vercomes the insulin dependency of glucokinase expression. Hepatic fatty ac id synthase and Spot-14 are insulin/glucose-dependent genes. For this latte r class of genes, the dominant positive form of SREBP-1c obviates the neces sity for the presence of insulin, whereas glucose potentiates the effect of SREBP-1c on their expression, In addition, the insulin dependency of lipid accumulation in cultured hepatocytes is overcome by the dominant positive form of SREBP-1c. We propose that SREBP-1c is a major mediator of insulin a ction on hepatic gene expression and a key regulator of hepatic glucose/lip id metabolism.