Involvement of a unique carbohydrate-responsive factor in the glucose regulation of rat liver fatty-acid synthase gene transcription

Refeeding carbohydrate to fasted rats induces the transcription of genes en coding enzymes of fatty acid biosynthesis, e.g. fatty-acid synthase (FAS). part of this transcriptional induction is mediated by insulin, An insulin r esponse element has been described for the fatty-acid synthase gene region of -600 to +65, but the 2-3-fold increase in fatty-acid synthase promoter a ctivity attributable to this region is small compared with the 20-30-fold i nduction in fatty-acid synthase gene transcription observed in fasted rats refed carbohydrate. We have previously reported that the fatty-acid synthas e gene region between -7382 and -6970 was essential for achieving high in v ivo rates of gene transcription. The studies of the current report demonstr ate that the region of -7382 to -6970 of the fatty-acid synthase gene conta ins a carbohydrate response element (CHO-REFAS) with a palindrome sequence (CATGTGn(5)GGCGTG) that is nearly identical to the CHO-RE of the L-type pyr uvate kinase and S-14 genes. The glucose responsiveness imparted by CHO-REF AS was independent of insulin. Moreover, CHO-REFAS conferred glucose respon siveness to a heterologous promoter (i.e. L-type pyruvate kinase). Electrop horetic mobility shift assays demonstrated that CHO-RE, readily bound a uni que hepatic ChoRF and that CHO-REFAS competed with the CHO-RE of the L-type pyruvate kinase and S-14 genes for ChoRF binding. In vivo footprinting rev ealed that fasting reduced and refeeding increased ChoRF binding to CHO-RE, . Thus, carbohydrate responsiveness of rat liver fatty-acid synthase appear s to require both insulin and glucose signaling pathways. More importantly, a unique hepatic ChoRF has now been shown to recognize glucose responsive sequences that are common to three different genes: fatty-acid synthase, L- type pyruvate kinase, and S-14.