Glucose regulation of the acetyl-CoA carboxylase promoter PI in rat hepatocytes

The rat acetyl-CoA carboxylase (ACC) alpha gene is transcribed from two pro moters, denoted PI and PII, that direct regulated expression in a tissue-sp ecific manner. Induction of ACC, the rate-controlling enzyme of fatty acid biosynthesis, occurs in the liver in response to feeding of a high carbohyd rate, low fat diet, conditions that favor enhanced lipogenesis. This induct ion is mainly due to increases in PI promoter activity. We have used primar y cultured hepatocytes from the rat to investigate glucose regulation of AC C expression. Glucose and insulin synergistically activated expression of A CC mRNAs transcribed from the PI promoter with little or no effect on PII m RNAs. Glucose treatment stimulated PI promoter activity in transfection ass ays and a glucose-regulated element was identified (-126/-102), homologous to those previously described in other responsive genes, including L-type p yruvate kinase, S-14 and fatty acid synthase. Mutation of this element elim inated the response to glucose. This region of the ACC PI promoter was able to bind a liver nuclear factor designated ChoRF that interacts with other conserved glucose-regulated elements. This ACC PI element is also capable o f conferring a strong response to glucose when linked to a heterologous pro moter. We conclude that induction of ACC gene expression under lipogenic co nditions in hepatocytes is mediated in part by the activation of a glucose- regulated transcription factor, ChoRF, which stimulates transcription from the PI promoter. Similar mechanisms operate on related genes permitting the coordinate induction of the lipogenic pathway.