Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency

Citrin Deficiency (CD) is caused by 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. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates 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 of de novo lipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to 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 drug candidates for both lean MASLD and support of urea cycle function in CD. Overall design: To determine whether deletion of NADH shuttle systems and/or provision of glycerol resulted in a ChREBP transcriptional program, we harvested livers from 40 mice representing water and glycerol-exposed males of the four genotypes, prepared cDNA and performed bulk paired-end 150 base-pair RNA sequencing (RNAseq)61 using an Illumina NovaSeq X Plus sequencer at >20 million paired reads per sample.