(A) Zhang et al. show that fructose-mediated activation of ChREBP in a normal liver results in increased DNL and promotes the degradation of SREBP2. This response is hepatoprotective, ultimately leading to an increase in hepatic triglyceride but no change in cholesterol levels. (B) On the other hand, mice lacking ChREBP do not accumulate excess triglycerides in their liver when fed a high-fructose diet. Because fatty acids and cholesterol share a common precursor, acetyl-CoA, carbon in fructose may flux toward cholesterol synthesis. Moreover, SREBP2 is activated in ChREBP-deficient hepatocytes to yield elevated hepatic cholesterol levels that predispose to maladaptive ER stress signaling, apoptosis, and hepatic injury.