SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice

Ying Yang, Michael A. Reid, Eric A. Hanse, Haiqing Li, Yuanding Li, Bryan I. Ruiz, Qi Fan and Mei Kong ()
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Ying Yang: University of California, Irvine
Michael A. Reid: Beckman Research Institute of City of Hope National Medical Center
Eric A. Hanse: University of California, Irvine
Haiqing Li: City of Hope National Medical Center
Yuanding Li: University of California, Irvine
Bryan I. Ruiz: University of California, Irvine
Qi Fan: University of California, Irvine
Mei Kong: University of California, Irvine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanisms underlying are not clear. Here, we demonstrate the serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is a negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Either whole-body or liver-specific deletion of SAPS3 protects male mice against HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout mice under HFD. Together, our results reveal that SAPS3 is a negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes.

Date: 2023
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DOI: 10.1038/s41467-023-36809-1

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