PPARα共抑制子NCoR1是脂肪酸β氧化和酮ogenesis的关键调节因子。然而，其调控机制主要尚不清楚。在这里，我们报告了致癌蛋白p21活化激酶4（PAK4）是NCoR1的激酶。具体而言，PAK4磷酸化了NCoR1的T1619/T2124位点，导致其在细胞核的定位和与PPARα的相互作用增加，从而抑制了PPARα的转录活性。我们观察到，在高脂饮食喂养的小鼠、NAFLD患者和肝细胞癌患者的肝组织中，酮生成受损，PAK4蛋白和NCoR1磷酸化水平增加。在小鼠中强制过度表达PAK4可抑制酮生成，从而增加肝脏脂肪蓄积，而PAK4的遗传消融或药物抑制呈现相反的表型。有趣的是，PAK4蛋白水平在禁食中显著降低，主要通过cAMP/PKA或Sirt1介导的泛素化和蛋白酶体降解来实现。通过这种方式，我们的发现提供了一个调控脂肪酸β氧化和酮ogenesis的PAK4-NCoR1/PPARα信号通路的证据。© 2023. Springer Nature Limited.

PPARα corepressor NCoR1 is a key regulator of fatty acid β-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 β-oxidation and ketogenesis.© 2023. Springer Nature Limited.