Liver ChREBP Protects Against Fructose-Induced Glycogenic Hepatotoxicity by Regulating L-Type Pyruvate Kinase

Area of Science:

• Metabolic disease research
• Hepatology
• Molecular biology

Background:

• Excessive fructose intake contributes to metabolic diseases.
• Carbohydrate response element-binding protein (ChREBP) is crucial for fructose tolerance.
• The role of liver ChREBP in fructose metabolism is not fully understood.

Purpose of the Study:

• To investigate the function of liver ChREBP in fructose metabolism and its protective role against fructose-induced liver injury.
• To elucidate the mechanisms by which liver ChREBP regulates glycogen metabolism and ATP homeostasis under high-fructose conditions.

Main Methods:

• Liver-specific ChREBP knockout mouse model.
• High-fructose diet feeding studies.
• Analysis of liver enzymes, glycogen content, ATP levels, and gene expression (LPK).

Main Results:

• Liver-specific ChREBP deficiency led to severe hepatotoxicity, hepatomegaly, and glycogen overload in mice on a high-fructose diet.
• ChREBP deficiency decreased liver ATP content, exacerbated by fructose.
• Increased glucose-6-phosphate (G6P) was observed in ChREBP-deficient livers, promoting glycogen synthesis.
• Hepatic LPK (liver pyruvate kinase) overexpression rescued these phenotypes.

Conclusions:

• Liver ChREBP plays a critical role in protecting the liver from fructose stress.
• ChREBP regulates hepatic glycogen metabolism and ATP homeostasis, mitigating fructose-induced hepatotoxicity.
• LPK is a key ChREBP target gene involved in this protective pathway.