Aryl hydrocarbon receptor (AhR) regulates adipocyte differentiation by assembling CRL4B ubiquitin ligase to target PPARγ for proteasomal degradation.
J Biol Chem
; 294(48): 18504-18515, 2019 11 29.
Article
em En
| MEDLINE
| ID: mdl-31653699
Peroxisome proliferator-activated receptor γ (PPARγ) is the central regulator of adipogenesis, and its dysregulation is linked to obesity and metabolic diseases. Identification of the factors that regulate PPARγ 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 PPARγ. 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 PPARγ. AhR overexpression reduced PPARγ 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 PPARγ are targeted for CRL4B-mediated ubiquitination, indicating cross-talk between acetylation and ubiquitination. Our findings establish a critical role of AhR in regulating PPARγ stability and suggest that the AhR-PPARγ interaction may represent a potential therapeutic target for managing metabolic diseases arising from PPARγ dysfunction.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
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Receptores de Hidrocarboneto Arílico
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Adipócitos
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Proteínas Culina
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Complexo de Endopeptidases do Proteassoma
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PPAR gama
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China