@cnspracklen.bsky.social did a nice set of GWAS scans to see what stands out in SLC25A13 carriers

in short, there are multiple signs of elevated FGF21 in this population

looks as though its not very deleterious to be a carrier though there could be gene-environment interactions that are hazardous

we teamed up!

Byungchang Jin used their HEK293T system to reconstitute ChREBP-Mlx-dependent transcription of ChoRE-luciferase constructs

by expressing GAPDH, GK & GPD1, they could alter levels of candidate ChREBP-activating metabolites & look at correlation w transcription

what about G3P? is it up when we delete NADH shuttle systems? and are hexose phosphates or pentose phosphates elevated consistent with other ideas of what turns on ChREBP?

by quantitative metabolomics, G3P doubles to almost 2 mM in liver. no change in hexose-Ps or pentose-Ps

then we looked for induction of the ChREBP transcriptional program with deletion of 1 or both shuttle systems & addition of glycerol

the ChREBP program is turned on by deletion of NADH shuttle systems & glycerol

many hypotheses to test!

we started by testing the hypothesis that deletion of NADH shuttle systems & addition of glyc elevate FGF21

Dr. Saheki & the Citrin Foundation kindly donated sperm from slc25a13 gpd2 mice

we made all the genotypes & tested FGF21 circulation w & wo glycerol

FGF21 is up!

there are convincing data that ChREBP mediates induction of FGF21 from carbohydrates. i started drawing diagrams that turned into Fig. 1

however, when he exposed them to real sucrose, they developed an aversion, consuming lesser amounts of sucrose, ethanol & glycerol than WT mice

i was walking my dog with this knowledge one day when i screamed FGF21!

we teamed up!

Byungchang Jin used their HEK293T system to reconstitute ChREBP-Mlx-dependent transcription of ChoRE-luciferase constructs

by expressing GAPDH, GK & GPD1, they could alter levels of candidate ChREBP-activating metabolites & look at correlation w transcription

what about G3P? is it up when we delete NADH shuttle systems? and are hexose phosphates or pentose phosphates elevated consistent with other ideas of what turns on ChREBP?

by quantitative metabolomics, G3P doubles to almost 2 mM in liver. no change in hexose-Ps or pentose-Ps

then we looked for induction of the ChREBP transcriptional program with deletion of 1 or both shuttle systems & addition of glycerol

the ChREBP program is turned on by deletion of NADH shuttle systems & glycerol

many hypotheses to test!

we started by testing the hypothesis that deletion of NADH shuttle systems & addition of glyc elevate FGF21

Dr. Saheki & the Citrin Foundation kindly donated sperm from slc25a13 gpd2 mice

we made all the genotypes & tested FGF21 circulation w & wo glycerol

FGF21 is up!

the brenner-knoller dogs