Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity

Intestinal, but not hepatic, ChREBP is required for fructose tolerance

“…This indicates that fructose can contribute to steatosis independently of DNL, and ChREBP. It has been suggested that ChREBP suppresses SREBP2, and ChREBP deficiency leads to induction of SREBP2 and its transcriptional targets involved in cholesterol biosynthesis (18). In contrast with this hypothesis, we did not observe an increase in Srebp2 mRNA expression in LiChKO mice ( Figure 3F).…”

“…HFrD did not increase aspartate aminotransferase (AST) in either genotype ( Figure 4A), although LiChKO mice fed HFrD had higher serum alanine aminotransferase (ALT) levels than their chow-fed counterparts ( Figure 4A). However, the ALT levels remained within the normative range and far below the 100-to 1,000-fold increase in ALT recently reported in global ChREBP-KO mice subjected to several weeks of HFrD (18). We next determined whether hepatic ChREBP was necessary to prevent fructose-induced hepatic ER stress.…”

“…Recently, Zhang et al, using global ChREBP-KO mice suggested that hepatic ChREBP is required to prevent fructose-induced endoplasmic reticulum (ER) stress and severe hepatotoxicity, and plays a protective role in the progression of steatosis to more advanced forms of NAFLD like nonalcoholic steatohepatitis (NASH) or cirrhosis (18).…”

Fructose metabolism and metabolic disease

“…Moreover, signaling elements in the ER stress response may contribute to NAFLD pathogenesis and progression (151). Recent work from Zhang et al suggests that ChREBP may protect the liver against fructose-induced ER stress and hepatic inflammation (152). However, we have recently observed that liver-specific ChREBP-knockout mice do not develop ER stress or hepatic inflammation when challenged with high-fructose diets (38).…”

ChREBP refines the hepatic response to fructose to protect the liver from injury

“…In this issue, Zhang and colleagues (18) have demonstrated that mice fed a high-fructose diet exhibit selective induction of ChREBP, but not SREBP1c, in the liver. Moreover, as previously described, mice lacking ChREBP were protected from high-fructose diet-induced increases in FASN, SCD1, and ACC1 expression in the liver and the development of hepatic steatosis, suggesting that SREBP1c is not sufficient to mediate the adverse effects associated with a high-fructose diet.…”