| First Author | Zhao Z | Year | 2018 |
| Journal | Hepatology | Volume | 68 |
| Issue | 1 | Pages | 289-303 |
| PubMed ID | 29331071 | Mgi Jnum | J:264679 |
| Mgi Id | MGI:6193790 | Doi | 10.1002/hep.29786 |
| Citation | Zhao Z, et al. (2018) Hepatic PPARalpha function is controlled by polyubiquitination and proteasome-mediated degradation through the coordinated actions of PAQR3 and HUWE1. Hepatology 68(1):289-303 |
| abstractText | Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPARalpha ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARalpha 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 PPARalpha target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism-modulating effects of PPARalpha. PAQR3 directly interacted with PPARalpha and increased the polyubiquitination and proteasome-mediated degradation of PPARalpha. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARalpha polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARalpha. CONCLUSION: Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARalpha in response to starvation. (Hepatology 2018;68:289-303). |
