Enzymes required for de novo lipogenesis are induced in mammalian liver after a 
meal high in carbohydrates. In addition to insulin, increased glucose metabolism 
initiates an intracellular signaling pathway that transcriptionally regulates 
genes encoding lipogenic enzymes. A cis-acting sequence, the carbohydrate 
response element (ChoRE), has been found in the promoter region of several of 
these genes. ChREBP (carbohydrate response element-binding protein) was recently 
identified as a candidate transcription factor in the glucose-signaling pathway. 
We reported that ChREBP requires the heterodimeric partner Max-like factor X 
(Mlx) to bind to ChoRE sequences. In this study we provide further evidence to 
support a direct role of Mlx in glucose signaling in the liver. We constructed 
two different dominant negative forms of Mlx that could dimerize with ChREBP but 
block its binding to DNA. When introduced into hepatocytes, both dominant 
negative forms of Mlx inhibited the glucose response of a transfected 
ChoRE-containing promoter. The glucose response was rescued by adding exogenous 
wild type Mlx or ChREBP, but not MondoA, a paralog of ChREBP that can also form 
a heterodimer with Mlx. Furthermore, dominant negative Mlx blocked the induction 
of glucose-responsive genes from their natural chromosomal context under high 
glucose conditions. In contrast, genes induced by the insulin and thyroid 
hormone-signaling pathways were unaffected by dominant negative Mlx. Mlx was 
present in the glucose-responsive complex of liver nuclear extract from which 
ChREBP was purified. In conclusion, Mlx is an obligatory partner of ChREBP in 
regulating lipogenic enzyme genes in liver.