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The E3 ubiquitin-protein ligase UHRF1 promotes adipogenesis and limits fibrosis by suppressing GPNMB-mediated TGF-β signaling.
- Source :
-
Scientific reports [Sci Rep] 2024 May 24; Vol. 14 (1), pp. 11886. Date of Electronic Publication: 2024 May 24. - Publication Year :
- 2024
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Abstract
- The E3 ubiquitin-ligase UHRF1 is an epigenetic regulator coordinating DNA methylation and histone modifications. However, little is known about how it regulates adipogenesis or metabolism. In this study, we discovered that UHRF1 is a key regulatory factor for adipogenesis, and we identified the altered molecular pathways that UHRF1 targets. Using CRISPR/Cas9-based knockout strategies, we discovered the whole transcriptomic changes upon UHRF1 deletion. Bioinformatics analyses revealed that key adipogenesis regulators such PPAR-γ and C/EBP-α were suppressed, whereas TGF-β signaling and fibrosis markers were upregulated in UHRF1-depleted differentiating adipocytes. Furthermore, UHRF1-depleted cells showed upregulated expression and secretion of TGF-β1, as well as the glycoprotein GPNMB. Treating differentiating preadipocytes with recombinant GPNMB led to an increase in TGF-β protein and secretion levels, which was accompanied by an increase in secretion of fibrosis markers such as MMP13 and a reduction in adipogenic conversion potential. Conversely, UHRF1 overexpression studies in human cells demonstrated downregulated levels of GPNMB and TGF-β, and enhanced adipogenic potential. In conclusion, our data show that UHRF1 positively regulates 3T3-L1 adipogenesis and limits fibrosis by suppressing GPNMB and TGF-β signaling cascade, highlighting the potential relevance of UHRF1 and its targets to the clinical management of obesity and linked metabolic disorders.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Humans
Mice
3T3-L1 Cells
Adipocytes metabolism
CCAAT-Enhancer-Binding Proteins metabolism
CCAAT-Enhancer-Binding Proteins genetics
Cell Differentiation
Eye Proteins metabolism
Eye Proteins genetics
Fibrosis
Transforming Growth Factor beta metabolism
Adipogenesis
Membrane Glycoproteins metabolism
Membrane Glycoproteins genetics
Signal Transduction
Ubiquitin-Protein Ligases metabolism
Ubiquitin-Protein Ligases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 38789534
- Full Text :
- https://doi.org/10.1038/s41598-024-62508-y