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Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell+Death+Dis 2017 ; 8 (12): ä Nephropedia Template TP
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CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPAR? and inhibit adipogenesis #MMPMID29233982
Jang MJ; Park UH; Kim JW; Choi H; Um SJ; Kim EJ
Cell Death Dis 2017[Dec]; 8 (12): ä PMID29233982show ga
Peroxisome proliferator-activated receptor ? (PPAR?) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite great progress in elucidating the transcriptional network of PPAR?, epigenetic regulation of this pathway by histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly bound to PPAR? through the co-repressor nuclear receptor (CoRNR) box 2 and repressed the transcriptional activity and adipogenic potential of PPAR?. Upon CACUL1 depletion, less SIRT1 and more LSD1 were recruited to the PPAR?-responsive gene promoter, leading to increased histone H3K9 acetylation, decreased H3K9 methylation, and PPAR? activation during adipogenesis in 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA sequencing supported the repressive role of CACUL1 in PPAR? activation and fat accumulation. Finally, we confirmed CACUL1 function in human adipose-derived stem cells. Overall, our data suggest that CACUL1 tightly regulates PPAR? signaling through the mutual opposition between SIRT1 and LSD1, providing insight into its potential use for anti-obesity treatment.