p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1

Abstract

PPAR alpha 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 PPAR alpha, thereby repressing the transcriptional activity of PPAR alpha. 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/PPAR alpha signaling pathway that regulates fatty acid beta-oxidation and ketogenesis. PPAR alpha corepressor NCoR1 is a key regulator of fatty acid beta-oxidation and ketogenesis. Here, the authors demonstrate that p21-activated kinase 4 phosphorylates NCoR1 at T1619/T2124, resulting in PPAR alpha transrepression and ketone body reduction.