Glycerol-3-Phosphate Drives Liver Fat and Sweet Aversion in Citrin Deficiency

Citrin deficiency is a rare autosomal recessive disorder affecting the SLC25A13 gene, which encodes a mitochondrial membrane transporter critical for the malate-aspartate shuttle (MAS) in hepatocytes. Loss of SLC25A13 blocks the cell's ability to transfer high-energy electrons (reducing equivalents) from cytosolic NADH into the mitochondrial matrix, causing cytosolic NADH to rise and disrupting carbohydrate oxidation. Clinically, patients present with neonatal jaundice resembling both urea cycle disorders and mitochondrial disease, and—strikingly—they exhibit a lifelong aversion to sweets and are prone to metabolic-dysfunction-associated steatotic liver disease (MASLD) despite being lean.

The research team hypothesized that accumulated glycerol-3-phosphate (G3P), a metabolite at the intersection of the glycerol-3-phosphate dehydrogenase shuttle and glycolysis, might be the molecular culprit. Using a double-knockout mouse model lacking both Slc25a13 and the complementary GPDS component Gpd2—which faithfully recapitulates human CD—the authors demonstrated that G3P builds up when both NADH shuttles are impaired. Crucially, they identified G3P as a direct activating ligand for ChREBP, the carbohydrate response element-binding protein, and showed that ChREBP activation drives robust transcription of FGF21 in the liver.

FGF21 is a secreted hormone with well-established roles in suppressing sweet and alcohol intake via β-klotho receptors in the brain, and in promoting lipogenesis and energy expenditure in peripheral tissues. The finding that G3P activates ChREBP to induce FGF21 elegantly explains the aversion to sweets and alcohol seen in CD patients and in the mouse model, as well as the paradoxical induction of FGF21 across seemingly contradictory metabolic states—including fasting, fructose feeding, ethanol consumption, obesity, mitochondrial disease, and refeeding. The authors propose that G3P accumulation is the common denominator: fasting triggers glycerol release from lipolysis (converted to G3P by glycerol kinase); fructolysis generates G3P from dihydroxyacetone phosphate and glyceraldehyde; and reductive stress from ethanol or mitochondrial dysfunction raises cytosolic NADH, shifting DHAP toward G3P.

Beyond resolving the FGF21 paradox, the study situates the G3P–ChREBP axis as a mechanistic component of the Randle Cycle—the classic competition between fatty acid and glucose oxidation—that contributes to MASLD. The authors also identify potential drug strategies: compounds that modulate G3P levels or mimic/antagonize its ChREBP-activating effect could serve as FGF21-inducing therapeutics for lean MASLD or as supports for urea cycle function in CD patients. The work provides a new framework for understanding how the liver communicates its metabolic state to the brain to modify dietary and substance use behaviors.

Caveats include reliance on a mouse model requiring dual gene knockout to phenocopy human CD, uncertainty about the precise molecular mechanism by which G3P engages ChREBP, and the need for larger human studies to validate G3P as the operative signal across all FGF21-inducing conditions.