Sugar Shockwaves: How the Fructose-Glucose-ChREBP Pathway Hijacks Liver Metabolism

Recent research establishes carbohydrate response element-binding protein (ChREBP) as a central regulator of fructose-induced hepatic lipogenesis, underscoring its critical role in mediating the effects of excessive sugar intake on liver metabolism. Consequently, this narrative review presents a perspective of hepatic sugar metabolism and ChREBP signaling, highlighting areas for further exploration to better understand and address the metabolic consequences of fructose-driven activation of ChREBP. The discussion encompasses five principal domains: (1) fructose metabolism; (2) the structure and function of ChREBP; (3) interactions between glucose and fructose metabolism with ChREBP activity; (4) mechanisms that intensify fructose's influence on ChREBP pathways; and (5) future research opportunities. Under physiological conditions, ChREBP mitigates accumulation of glycolytic intermediates; however, excessive sugar consumption overwhelms these capacities, thereby increasing lipogenesis. Fructose demonstrates notably stronger activation of ChREBP in vivo relative to glucose. Given ChREBP's dual role in maintaining metabolic homeostasis and promoting insulin resistance under high fructose intake, therapeutic targeting poses considerable challenges. We propose the testable hypothesis that the MG generated from excessive fructose metabolism may bind to ChREBP's lysine residues, stabilizing the protein and reducing degradation by impeding ubiquitination. This stabilization of ChREBP would prolong its activity, thereby further promoting sustained hepatic lipogenesis and exacerbating the risk of MASLD. Experimental and clinical research is needed to confirm its validity and define the molecular pathways involved. Future studies should aim to identify glucose metabolites involved in ChREBP regulation and clarify its beneficial versus adverse effects. The specific functions and regulation of ChREBPβ vs. ChREBPα remain to be elucidated.