Language
English
Publication Date
11-1-2025
Journal
Nature Metabolism
DOI
10.1038/s42255-025-01399-3
PMID
41238906
PMCID
PMC12638245
PubMedCentral® Posted Date
11-14-2025
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Fibroblast Growth Factors, Animals, Lipogenesis, Mice, Humans, Glycerophosphates, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Calcium-Binding Proteins, Organic Anion Transporters, Transcription, Genetic, Fatty Liver, Mitochondrial Membrane Transport Proteins, Mice, Knockout, Mice, Inbred C57BL, Metabolic diseases, Gene regulation, Transcriptional regulatory elements, Metabolism, Liver
Published Open-Access
yes
Recommended Citation
Tiwari, Vinod; Jin, Byungchang; Sun, Olivia; et al., "Glycerol-3-Phosphate Activates ChREBP, FGF21 Transcription and Lipogenesis in Citrin Deficiency" (2025). Faculty and Staff Publications. 4912.
https://digitalcommons.library.tmc.edu/baylor_docs/4912
Included in
Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Microbiology Commons