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Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1
Author(s) -
Zhao Zilong,
Xu Daqian,
Wang Zheng,
Wang Lin,
Han Ruomei,
Wang Zhenzhen,
Liao Lujian,
Chen Yan
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29786
Subject(s) - ubiquitin ligase , ubiquitin , peroxisome proliferator activated receptor , peroxisome , microbiology and biotechnology , nuclear receptor , chemistry , gene knockdown , catabolism , biochemistry , proteasome , receptor , ketogenesis , transcription factor , biology , metabolism , gene , ketone bodies
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 posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (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 enhanced the fasting‐induced expression of PPARα target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism‐modulating effects of PPARα. PAQR3 directly interacted with PPARα and increased the polyubiquitination and proteasome‐mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARα. Conclusion: Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (H epatology 2018;68:289‐303).