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Updated: Jul 19, 2025

Measuring the Rate of Lipolysis in Ex Vivo Murine Adipose Tissue and Primary Preadipocytes Differentiated In Vitro
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p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1

Min Yan Shi1, Hwang Chan Yu1, Chang Yeob Han2

  • 1Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, 54896, Republic of Korea.

Nature Communications
|August 17, 2023
PubMed

Insights

Oncoprotein p21-activated kinase 4 (PAK4) phosphorylates NCoR1, repressing fatty acid oxidation and ketogenesis. PAK4 levels decrease with fasting, suggesting a pathway for regulating hepatic fat metabolism.

Area of Science:

  • Metabolism
  • Molecular Biology
  • Cell Signaling

Background:

  • Nuclear receptor corepressor 1 (NCoR1) is crucial for regulating fatty acid metabolism.
  • The precise molecular mechanisms governing NCoR1 activity remain largely unelucidated.

Purpose of the Study:

  • To identify kinases that regulate NCoR1.
  • To elucidate the role of p21-activated kinase 4 (PAK4) in NCoR1-mediated regulation of fatty acid metabolism.

Main Methods:

  • Phosphorylation site mapping of NCoR1.
  • In vivo studies using high-fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients.
  • Genetic manipulation (overexpression, ablation) and pharmacological inhibition of PAK4 in mice.
  • Analysis of PAK4 protein degradation pathways.

Main Results:

  • PAK4 phosphorylates NCoR1 at T1619/T2124, enhancing its nuclear localization and PPARα interaction.
  • PAK4 overexpression impairs ketogenesis and promotes hepatic fat accumulation.
  • PAK4 levels are reduced by fasting via ubiquitination and proteasomal degradation.
  • Elevated PAK4 and NCoR1 phosphorylation are observed in high-fat diet models, NAFLD, and HCC.

Conclusions:

  • A novel signaling pathway involving PAK4, NCoR1, and PPARα regulates fatty acid oxidation and ketogenesis.
  • PAK4 acts as a key regulator of hepatic lipid metabolism.
  • PAK4 activity is modulated by fasting through regulated protein degradation.

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