Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P–ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. In a mouse model of the rare disease citrin deficiency, the authors discovered that the accumulation of glycerol-3-phosphate leads to ChREBP activation and FGF21 induction. The study identifies glycerol-3-phosphate as a ChREBP-activating ligand, which could resolve paradoxes of FGF21 expression and clarify the logic of lipogenic transcription.