Fig. 1: Inductive reasoning of a G3P–ChREBP–FGF21 transcription system in hepatocytes.

FGF21 is induced in a wide variety of conditions that have eluded a unified theory of induction. The following diagrams of metabolite flow in hepatocytes as affected by conditions of metabolic stress led us to propose G3P as the activator of ChREBP that can resolve the paradoxes of FGF21. a, The metabolic flow in unperturbed hepatocytes is facilitated by two NADH shuttles without the induction of FGF21. The MAS¹ facilitates the transfer of reducing equivalents from cytosolic NADH to oxaloacetate, transiently forming malate, which is reoxidized at complex I in the mitochondrial matrix. The GPDS¹³ facilitates the transfer of reducing equivalents from cytosolic NADH to DHAP, transiently forming G3P with reducing equivalents transferred to FAD, forming FADH₂, which is reoxidized with electron transfer to coenzyme Q in the mitochondrial electron transfer chain (METC). b, With either mitochondrial insufficiency, disruption of the MAS in CD, disruption of the GPDS, ethanol metabolism or elevated glucose, cytosolic NADH is expected to rise, which would be expected to cause the accumulation of G3P, which we propose to be the activator of ChREBP, driving the FGF21 expression. c, Fructolysis is predicted to elevate G3P, with one G3P equivalent formed from DHAP and another formed from glyceraldehyde (GA) via the function of alcohol dehydrogenase (ADH) and glycerol kinase¹⁰⁷. The resulting G3P is proposed as the activating ligand for ChREBP activation and FGF21 expression. d, Triglyceride lipolysis is expected to produce glycerol and free fatty acids. Conversion of glycerol to G3P is proposed to activate ChREBP, which would co-operate with free fatty-acid-activated PPARα to drive transcription of FGF21. OAA, oxaloacetate; α-KG, α-ketoglutarate; 1,3-BPG, 1-3-bisphosphoglycerate; FFA, free fatty acid. Figure created with BioRender.com.