CACUL1 reciprocally regulates SIRT1 and LSD1 for PPAR? repression and anti-adipogenesis

Peroxisome proliferator-activated receptor ? (PPAR?) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite a large progress on the transcriptional network of PPAR?, the epigenetic regulation associated with histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly binds to PPAR? through the CoRNRbox 2 and represses the transcription activity and adipogenic potential of PPAR?. Upon CACUL1 depletion, less SIRT1 and more LSD1 was recruited to the PPAR?-responsive gene promoter, leading to the increased histone H3K9 acetylation and decreased H3K9 methylation for PPAR? activation during adipogenesis of 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA-seq supported the repressive role of CACUL1 in PPAR? activation and fat accumulation. Finally, we confirmed the CACUL1 function in human adipose-derived stem cells. Overall, our data suggest thatCACUL1 tightly regulates PPAR? signaling through the mutual opposition between SIRT1 and LSD1, providing additional insight into its use for anti-obesity treatment.

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