Hepatic PPARα function is controlled by polyubiquitination and proteasome-mediated degradation via the coordinated actions of PAQR3 and HUWE1

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by post-translational modification is poorly understood. Here, we identified that PAQR3 promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus-mediated Paqr3 knockdown and liver-specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhances the fasting-induced expression of PPARα target genes, including those involved in fatty acid oxidation and FGF21, a key molecule that mediates the metabolism-modulating effects of PPARα. PAQR3 directly interacts with PPARα and increases the polyubiquitination and proteasome-mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhances the interaction between HUWE1 and PPARα. Collectively, this study revealed that ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. This article is protected by copyright. All rights reserved.

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