| First Author | Dou H | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 48 | Pages | 18504-18515 |
| PubMed ID | 31653699 | Mgi Jnum | J:283071 |
| Mgi Id | MGI:6383615 | Doi | 10.1074/jbc.RA119.009282 |
| Citation | Dou H, et al. (2019) Aryl hydrocarbon receptor (AhR) regulates adipocyte differentiation by assembling CRL4B ubiquitin ligase to target PPARgamma for proteasomal degradation. J Biol Chem 294(48):18504-18515 |
| abstractText | Peroxisome proliferator-activated receptor gamma (PPARgamma) is the central regulator of adipogenesis, and its dysregulation is linked to obesity and metabolic diseases. Identification of the factors that regulate PPARgamma expression and activity is therefore crucial for combating obesity. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with a known role in xenobiotic detoxification. Recent studies have suggested that AhR also plays essential roles in energy metabolism. However, the detailed mechanisms remain unclear. We previously reported that experiments with adipocyte-specific Cullin 4b (Cul4b)-knockout mice showed that CUL4B suppresses adipogenesis by targeting PPARgamma. Here, using immunoprecipitation, ubiquitination, real-time PCR, and GST-pulldown assays, we report that AhR functions as the substrate receptor in CUL4B-RING E3 ubiquitin ligase (CRL4B) complex and is required for recruiting PPARgamma. AhR overexpression reduced PPARgamma stability and suppressed adipocyte differentiation, and AhR knockdown stimulated adipocyte differentiation in 3T3-L1 cells. Furthermore, we found that two lysine sites on residues 268 and 293 in PPARgamma are targeted for CRL4B-mediated ubiquitination, indicating cross-talk between acetylation and ubiquitination. Our findings establish a critical role of AhR in regulating PPARgamma stability and suggest that the AhR-PPARgamma interaction may represent a potential therapeutic target for managing metabolic diseases arising from PPARgamma dysfunction. |
