p21-activated kinase 4 suppresses fatty acid ß-oxidation and ketogenesis by phosphorylating NCoR1.
Nat Commun
; 14(1): 4987, 2023 08 17.
Article
em En
| MEDLINE
| ID: mdl-37591884
ABSTRACT
PPARα corepressor NCoR1 is a key regulator of fatty acid ß-oxidation and ketogenesis. However, its regulatory mechanism is largely unknown. Here, we report that oncoprotein p21-activated kinase 4 (PAK4) is an NCoR1 kinase. Specifically, PAK4 phosphorylates NCoR1 at T1619/T2124, resulting in an increase in its nuclear localization and interaction with PPARα, thereby repressing the transcriptional activity of PPARα. We observe impaired ketogenesis and increases in PAK4 protein and NCoR1 phosphorylation levels in liver tissues of high fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients. Forced overexpression of PAK4 in mice represses ketogenesis and thereby increases hepatic fat accumulation, whereas genetic ablation or pharmacological inhibition of PAK4 exhibites an opposite phenotype. Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid ß-oxidation and ketogenesis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
PPAR alfa
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Quinases Ativadas por p21
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Ácidos Graxos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article