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

Min Yan Shi, Hwang Chan Yu, Chang Yeob Han, In Hyuk Bang, Ho Sung Park, Kyu Yun Jang, Sangkyu Lee, Jeong Bum Son, Nam Doo Kim, Byung-Hyun Park () and Eun Ju Bae ()
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Min Yan Shi: Jeonbuk National University Medical School
Hwang Chan Yu: Jeonbuk National University Medical School
Chang Yeob Han: Jeonbuk National University
In Hyuk Bang: Jeonbuk National University Medical School
Ho Sung Park: Jeonbuk National University Medical School
Kyu Yun Jang: Jeonbuk National University Medical School
Sangkyu Lee: Sungkyunkwan University
Jeong Bum Son: VORONOI BIO Inc.
Nam Doo Kim: VORONOI BIO Inc.
Byung-Hyun Park: Jeonbuk National University Medical School
Eun Ju Bae: Jeonbuk National University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40597-z

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