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FGF2 mediated USP42-PPAR axis activation ameliorates liver oxidative damage and promotes regeneration

ABSTRACT: Liver regeneration is critical for maintaining whole-body homeostasis, especially under the exposure to deadly chemical toxins. Understanding the molecular mechanisms underlying liver repair is critical for the development of intervention strategies to treat liver diseases. In this study, we identified ubiquitin-specific Proteases 42 (USP42) as a novel deubiquitinases (DUB) of peroxisome proliferators-activated receptor γ (PPARγ) in hepatocytes. This DUB interacted, deubiquitinated and stabilized PPARγ, and increased PPAR targeted proliferative and anti-oxidative gene expressions, which protects liver from carbon tetrachloride (CCL4) induced oxidative injury and promotes liver regeneration. In addition, fibroblast growth factor 2 (FGF2) initiated USP42 expression and enhanced the interaction between USP42 and PPARduring liver regeneration process. Moreover, the PPARfull agonist, rosiglitazone (RSG), possesses the ability to further reinforce the USP42-PPARinterplay, which enlightens us to construct an extracellular vesicle-based targeting strategy to activate liver USP42-PPAR axis and promote liver regeneration. In summary, our work uncovers the importance of USP42-PPAR axis mediated liver tissue homeostasis, and provides a promising regimen to target this protein-protein interplay for liver regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE286997 | GEO | 2025/01/15

REPOSITORIES: GEO

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Project description:Metabolic challenges experienced by dairy cows during the transition between pregnancy and lactation (also known as peripartum), are of considerable interest from a nutrigenomic perspective. The mobilization of large amounts of non-esterified fatty acids (NEFA) leads to an increase in NEFA uptake in the liver, the excess of which can cause hepatic accumulation of lipids and ultimately fatty liver. Interestingly, peripartum NEFA activate the peroxisome proliferator-activated receptor (PPAR), a transcriptional regulator with known nutrigenomic properties. The study of PPAR activation in the liver of periparturient dairy cows is thus crucial; however, current in vitro models of the bovine liver are inadequate, and the isolation of primary hepatocytes is prohibitive and error-prone. The objective of the current study was to evaluate the use of precision-cut liver slices (PCLS) from liver biopsies as a model for PPAR activation in periparturient dairy cows. Four cows were enrolled in the experiment, and PCLS from each were prepared prepartum (-10 DIM) and postpartum (+10 DIM) and treated with a variety of PPAR agonists and antagonist. Gene expression was assayed through RT-qPCR and RNAseq, and intracellular triglyceride concentration was measured. PCLS treated with PPARγ agonist rosiglitazone displayed upregulation of canonical PPAR targets ACADVL and LIPC in the postpartum, while a PPARδ agonists increased expression of PPAR target PDK4; no gene expression changes were detected in the prepartum, and triglyceride concentrations were unchanged between treatments. Transcriptome sequencing revealed considerable differences in response to PPAR agonist, mainly related to pathways involved with lipid metabolism and the immune response. Among differentially expressed genes, a subset of 91 genes were identified as novel putative PPAR targets in the bovine liver, by cross-referencing our results with a publicly-available dataset of predicted PPAR target genes, and supplementing our finding with prior literature. Our results provide important insights on the use of PCLS as a model for assaying PPAR activation in the peripartum.

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FGF2 mediated USP42-PPAR axis activation ameliorates liver oxidative damage and promotes regeneration

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