Elevated FGF21 and triglycerides in SLC25A13 carriers support the G3P-ChREBP Citrin Deficiency disease hypothesis

BackgroundPeople with Citrin Deficiency (CD), inactivated for both copies of SLC25A13, have lean metabolic dysfunction-associated steatotic liver disease (MASLD) and an aversion to sweets. The mouse model of CD, which inactivates Slc25a13 and Gpd2, has been shown to elevate hepatic glycerol-3-phosphate (G3P) and activate carbohydrate response element binding protein (ChREBP) thereby increasing lipogenic transcription, which could account for MASLD, and circulation of FGF21, which could account for sweet aversion. Because the G3P-ChREBP hypothesis of CD was supported only by mouse data, the objective of this study was to determine if people with one or two copies of SLC25A13 inactivated have higher circulating FGF21 and whether higher FGF21 is associated with higher circulating lipids in this population, consistent with a common driver of sweet aversion and lipogenesis. MethodsBlood and urine from age- and sex-matched participants in the Taiwan biobank were selected and used to test the hypothesis that SLC25A13 inactivation elevates circulating FGF21 and urinary sodium and to determine whether elevated FGF21 correlates with elevated circulating triglycerides in carriers of SLC25A13 mutations. ResultsAge-matched male and female SLC25A13 mutation carriers have 2.2-fold and 2.8-fold higher circulating FGF21 than control individuals with results significant at P = 0.056 and 0.012, respectively. CD patients and mutation carriers also had elevated urinary sodium (P = 0.0052) and CD patients have greatly elevated circulating FGF21. Moreover, though higher FGF21 depresses circulating lipids in the general population, higher FGF21 was strongly correlated with higher circulating triglycerides in SLC25A13 mutation carriers. ConclusionHuman data support insights gleaned from the mouse model of CD: that loss of SLC25A13 drives both lipogenic transcription and circulation of FGF21.