Description
Epidemiologic and animal studies implicate overconsumption of fructose in the development of non-alcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remains largely unknown. We present evidence supporting the essential function of the lipogenic transcription factor ChREBP in mediating adaptation response to fructose and protecting against fructose-induced hepatotoxicity. High-fructose diet (HFrD) activates hepatic lipogenesis via a ChREBP-dependent manner in wildtype mice, while inducing steatohepatitis in Chrebp-KO mice. In Chrebp-KO mouse livers, HFrD reduces levels of molecular chaperones and activates the CHOP-dependent unfolded protein response, whereas administration of chemical chaperone or Chop shRNA rescues liver injury. Gene expression profiling revealed elevated expression of cholesterol biosynthesis genes in Chrebp-KO livers after HFrD, in parallel with increased abundance of nuclear SREBP2.