Hepatic ChREBP reciprocally modulates systemic insulin sensitivity in NAFLD

Area of Science:

• Metabolic regulation
• Molecular biology
• Hepatology

Background:

• The role of carbohydrate-responsive element-binding protein (ChREBP) in hepatic insulin sensitivity is not fully understood.
• Insulin resistance is a hallmark of metabolic disorders like non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM).

Purpose of the Study:

• To investigate the impact of hepatic ChREBP on insulin sensitivity.
• To identify molecular mechanisms linking ChREBP to insulin resistance.
• To explore therapeutic strategies targeting ChREBP for metabolic diseases.

Main Methods:

• Utilized high-fat and sucrose-fed mouse models with hepatic ChREBP knockdown.
• Investigated transcriptional regulation of PTEN by ChREBP.
• Analyzed FGF21 release and systemic insulin sensitivity.
• Employed molecular dynamics simulations to identify small molecules targeting ChREBP.
• Tested Quercetin's efficacy in vivo.

Main Results:

• Hepatic ChREBP depletion significantly improved insulin sensitivity in mice.
• ChREBP directly drives the transcriptional induction of hepatic PTEN.
• Reduced PTEN levels promote hepatic insulin sensitivity and enhance FGF21 release, improving systemic insulin sensitivity.
• Quercetin effectively sequesters ChREBP in the cytosol, preventing its nuclear translocation and mimicking the insulin-sensitizing effects of ChREBP knockdown.

Conclusions:

• Hepatic ChREBP is a critical regulator of systemic insulin signaling.
• Downregulation of ChREBP offers a protective mechanism against insulin resistance.
• Quercetin represents a potential therapeutic agent for managing insulin resistance by targeting liver ChREBP.