Retinoic acid （RA）, a bioactive metaboUte of vitamin A, is a critical mediator of cell differentiation. RA blocks adipogenesis, but mechanisms remain to be established. ZFP423 is a key transcription factor maintaini...Retinoic acid （RA）, a bioactive metaboUte of vitamin A, is a critical mediator of cell differentiation. RA blocks adipogenesis, but mechanisms remain to be established. ZFP423 is a key transcription factor maintaining white adipose identity. We found that RA inhibits Zfp423 expression and adipogenesis via blocking DNA demethylation in the promoter of Zfp423, a process mediated by growth arrest and DNA-damage-inducible protein alpha （GADD45A）. RA induces the partnering between retinoic acid receptor （PAR） and tumor suppressor inhibitor of growth protein 1 （ING1）, which prevents the formation of GADD45A and ING1 complex necessary for locus-specific Zfp423 DNA demethylation. In vivo, vitamin A supplementation prevents obesity, downregulates Godd45a expression, and reduces GADD45A binding and DNA demethylation in the Zfp423 promoter. Inhibition of Zfp423 expres- sion due to PA contributes to the enhanced brown adipogenesis. In summary, PA inhibits white adipogenesis by inducing PAR and ING1 interaction and inhibiting Godd45a expression, which prevents GADD45A-mediated DNA demethylation.展开更多
文摘Retinoic acid （RA）, a bioactive metaboUte of vitamin A, is a critical mediator of cell differentiation. RA blocks adipogenesis, but mechanisms remain to be established. ZFP423 is a key transcription factor maintaining white adipose identity. We found that RA inhibits Zfp423 expression and adipogenesis via blocking DNA demethylation in the promoter of Zfp423, a process mediated by growth arrest and DNA-damage-inducible protein alpha （GADD45A）. RA induces the partnering between retinoic acid receptor （PAR） and tumor suppressor inhibitor of growth protein 1 （ING1）, which prevents the formation of GADD45A and ING1 complex necessary for locus-specific Zfp423 DNA demethylation. In vivo, vitamin A supplementation prevents obesity, downregulates Godd45a expression, and reduces GADD45A binding and DNA demethylation in the Zfp423 promoter. Inhibition of Zfp423 expres- sion due to PA contributes to the enhanced brown adipogenesis. In summary, PA inhibits white adipogenesis by inducing PAR and ING1 interaction and inhibiting Godd45a expression, which prevents GADD45A-mediated DNA demethylation.
