ArticleHepatology (Baltimore, Md.)2018
Hepatic PPARα function is controlled by polyubiquitination and proteasome-mediated degradation through the coordinated actions of PAQR3 and HUWE1.
Article in Hepatology (Baltimore, Md.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- All-trans retinoic acid suppresses systemic inflammation induced by severe fever with thrombocytopenia syndrome virus in mice.Nature microbiology · 2026Article
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- A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review).International journal of molecular medicine · 2026Review
- RNF128 regulates the adaptive metabolic response to fasting by modulating PPARα function.Cell death and differentiation · 2026Article
- Microbiota-derived IPA protects against colitis by regulating intestinal HMGCS2-mediated ketogenesis to facilitate mucosal healing.Nature communications · 2026Article
- Emerging Approaches for the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease: The Application of Nanomedicines.International journal of nanomedicine · 2026Review
- Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- From mechanisms to management: Early detection and improved treatment of MASLD and its related hepatocellular carcinoma.Hepatology communications · 2025Review
- Identification and validation of autophagy-related genes in sepsis based on bioinformatics studies.Virology journal · 2025Article
- Review
- The role of ubiquitination and deubiquitination in cancer lipid metabolism.Frontiers in oncology · 2025Review
- LIFR regulates cholesterol-driven bidirectional hepatocyte-neutrophil cross-talk to promote liver regeneration.Nature metabolism · 2024Article
- Retinoid X receptor heterodimers in hepatic function: structural insights and therapeutic potential.Frontiers in pharmacology · 2024Review
- HepaticiScience · 2023Article
- Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.Nature communications · 2023Article
- E3 ubiquitin ligases in cancer stem cells: key regulators of cancer hallmarks and novel therapeutic opportunities.Cellular oncology (Dordrecht, Netherlands) · 2023Review
- Hepatotoxic Components Effect ofMolecules (Basel, Switzerland) · 2023Article
- Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARα-regulated gene transcription and tumour growth.Nature cell biology · 2022Article
- Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism.Acta pharmaceutica Sinica. B · 2022Article
- Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice.Nature communications · 2022Article
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
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 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.
conclusionUbiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (Hepatology 2018;68:289-303).
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