| First Author | Shi MY | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 4987 |
| PubMed ID | 37591884 | Mgi Jnum | J:357550 |
| Mgi Id | MGI:7521423 | Doi | 10.1038/s41467-023-40597-z |
| Citation | Shi MY, et al. (2023) p21-activated kinase 4 suppresses fatty acid beta-oxidation and ketogenesis by phosphorylating NCoR1. Nat Commun 14(1):4987 |
| abstractText | PPARalpha corepressor NCoR1 is a key regulator of fatty acid beta-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 PPARalpha, thereby repressing the transcriptional activity of PPARalpha. 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/PPARalpha signaling pathway that regulates fatty acid beta-oxidation and ketogenesis. |
