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Regulation of adipocyte differentiation by clusterin-mediated Krüppel-like factor 5 stabilization.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Dec; Vol. 34 (12), pp. 16276-16290. Date of Electronic Publication: 2020 Oct 20. - Publication Year :
- 2020
-
Abstract
- Clusterin (CLU) is a heterodimeric glycoprotein involved in a range of biological processes. We investigated the function of CLU as a novel regulator of adipogenesis. CLU expression increased during 3T3-L1 preadipocyte differentiation. CLU overexpression promoted adipogenic differentiation of preadipocytes and increased the mRNA levels of adipogenic markers including peroxisome proliferator-activated receptor γ (Pparg) and CCAAT enhancer-binding protein α (Cebpa). Conversely, knockdown of CLU attenuated adipogenesis and reduced transcript levels of Pparg and Cebpa. However, the promoter activities of both the Pparg and the Cebpa gene were not affected by alteration of CLU expression on its own. Additionally, the protein level of Krüppel-like factor 5 (KLF5), an upstream transcription factor of Pparg and Cebpa involved in adipogenic differentiation, was upregulated by CLU overexpression, although the mRNA level of Klf5 was not altered by changes in the expression level of CLU. Cycloheximide chase assay showed that the increased level of KLF5 by CLU overexpression was due to decreased degradation of KLF5 protein. Interestingly, CLU increased the stability of KLF5 by decreasing KLF5 ubiquitination. CLU inhibited the interaction between KLF5 and F-box/WD repeat-containing protein 7, which is an E3 ubiquitin ligase that targets KLF5. The adipogenic role of CLU was also addressed in mesenchymal stem cells (MSCs) and Clu <superscript>-/-</superscript> mouse embryonic fibroblasts (MEFs). Furthermore, CLU enhanced KLF5-mediated transcriptional activation of both the Cebpa and the Pparg promoter. Taken together, these results suggest that CLU is a novel regulator of adipocyte differentiation by modulating the protein stability of the adipogenic transcription factor KLF5.<br /> (© 2020 Federation of American Societies for Experimental Biology.)
- Subjects :
- 3T3-L1 Cells
Adipogenesis genetics
Animals
Cell Line
Fibroblasts physiology
Humans
Male
Mice
Mice, Inbred C57BL
Promoter Regions, Genetic genetics
Transcriptional Activation genetics
Ubiquitin-Protein Ligases genetics
Ubiquitination genetics
Adipocytes physiology
Cell Differentiation genetics
Clusterin genetics
Kruppel-Like Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 34
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 33078455
- Full Text :
- https://doi.org/10.1096/fj.202000551RR