Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, 54896, Republic of Korea.
School of Pharmacy, Jeonbuk National University, Jeonju, 54896, Republic of Korea.
Nat Commun. 2023 Aug 17;14(1):4987. doi: 10.1038/s41467-023-40597-z.
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.
过氧化物酶体增殖物激活受体α辅抑制因子 NCoR1 是脂肪酸β氧化和酮体生成的关键调节因子。然而，其调节机制在很大程度上尚不清楚。在这里，我们报告癌蛋白 p21 激活激酶 4（PAK4）是 NCoR1 的一种激酶。具体而言，PAK4 磷酸化 NCoR1 的 T1619/T2124，导致其核定位增加，并与 PPARα相互作用，从而抑制 PPARα 的转录活性。我们观察到高脂饮食喂养的小鼠、非酒精性脂肪性肝病患者和肝细胞癌患者的肝脏组织中酮体生成减少，PAK4 蛋白和 NCoR1 磷酸化水平升高。在小鼠中强制过表达 PAK4 会抑制酮体生成，从而增加肝脂肪堆积，而 PAK4 的基因缺失或药理学抑制则表现出相反的表型。有趣的是，禁食可显著抑制 PAK4 蛋白水平，主要通过 cAMP/PKA 或 Sirt1 介导的泛素化和蛋白酶体降解。通过这种方式，我们的研究结果为调节脂肪酸β氧化和酮体生成的 PAK4-NCoR1/PPARα 信号通路提供了证据。
