Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver

In the liver, transcription of several genes encoding lipogenic and glycoly tic enzymes, in particular the gene for fatty acid synthase (FAS), is known to be stimulated by dietary carbohydrates. The molecular dissection of the FAS promoter pointed out the critical role of an E box motif, located at p osition -65 with respect to the start site of transcription, in mediating t he glucose- and insulin-dependent regulation of the gene. Upstream stimulat ory factors (USF1 and USF2) and sterol response element binding protein 1 ( SREBP1) were shown to be able to interact in vitro with this E box. However , to date, the relative contributions of USFs and SREBP1 ex vivo remain con troversial. To gain insight into the specific roles of these factors in viv o, we have analyzed the glucose responsiveness of hepatic FAS gene expressi on in USF1 and USF2 knock-out mice. In both types of mouse lines, defective in either USF1 or USF2, induction of the FAS gene by refeeding a carbohydr ate rich diet was severely delayed, whereas expression of SBEBP1 was almost normal and insulin response unchanged. Therefore, USF transactivators, and especially USF1/USF2 heterodimers, seem to be essential to sustain the die tary induction of the FAS gene in the liver.