Glycerol-3-phosphate Activates ChREBP, FGF21 Transcription and Lipogenesis in Citrin Deficiency

Overview

Journal bioRxiv

Date 2025 Jan 7

PMID 39763913

Authors

Vinod Tiwari

Byungchang Jin

Olivia Sun

Edwin D J Lopez Gonzalez

Min-Hsuan Chen

Xiwei Wu

Hardik Shah

Andrew Zhang

Mark A Herman

Cassandra N Spracklen

Russell P Goodman

Charles Brenner

Affiliations

Soon will be listed here.

Abstract

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 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 drug candidates for both lean MASLD and support of urea cycle function in CD.

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