Hepatic ChREBP reciprocally modulates systemic insulin sensitivity in NAFLD

The relation between hepatic ChREBP level and insulin sensitivity remains equivocal. Our study, however, provides compelling evidence that hepatic ChREBP depletion can significantly enhance insulin sensitivity in high-fat and sucrose-fed mice. We have identified that transcriptional induction of hepatic PTEN is driven by ChREBP. Mechanistically, two critical stimuli are elicited in the hepatic ChREBP knockdown condition. The PTEN level is reduced for one stimulus, thereby promoting hepatic insulin sensitivity. The second stimulus, where reduced hepatic PTEN leads to the enhanced release of FGF21, spreads systemic insulin sensitivity. These findings identify hepatic ChREBP as a critical modulator of systemic insulin signaling and suggest that ChREBP downregulation may lead to protection against insulin resistance. Building on this, our molecular dynamics simulation analysis has led to the discovery of a small molecule, Quercetin, that sequesters ChREBP in the cytosol. We report that Quercetin treatment can sequester ChREBP in the cytosol and abrogate high-fat and sucrose-fed–mediated ChREBP nuclear translocation, thereby mimicking the insulin-sensitizing abilities of the hepatic ChREBP knockdown condition. These findings have significant therapeutic implications, suggesting that liver-selective downregulation of ChREBP could protect against systemic insulin resistance that frequently develops early in the pathogenesis of NAFLD and T2DM.