Regulation of adipocyte differentiation by clusterin‐mediated Krüppel‐like factor 5 stabilization

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 preadi...

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Veröffentlicht in:The FASEB journal 2020-12, Vol.34 (12), p.16276-16290
Hauptverfasser: Oh, Gyun‐Sik, Yoon, Jin, Kim, Gukhan, Kim, Geun Hyang, Kim, Dong Seop, Choi, Bongkun, Chang, Eun‐Ju, Lee, Eun‐Sook, Kim, Seung‐Whan
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container_issue 12
container_start_page 16276
container_title The FASEB journal
container_volume 34
creator Oh, Gyun‐Sik
Yoon, Jin
Kim, Gukhan
Kim, Geun Hyang
Kim, Dong Seop
Choi, Bongkun
Chang, Eun‐Ju
Lee, Eun‐Sook
Kim, Seung‐Whan
description 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−/− 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.
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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−/− mouse embryonic fibroblasts (MEFs). Furthermore, CLU enhanced KLF5‐mediated transcriptional activation of both the Cebpa and the Pparg promoter. 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source MEDLINE; Access via Wiley Online Library; Alma/SFX Local Collection
subjects 3T3-L1 Cells
Adipocytes - physiology
adipogenesis
Adipogenesis - genetics
Animals
Cell Differentiation - genetics
Cell Line
clusterin
Clusterin - genetics
Fibroblasts - physiology
Humans
Kruppel-Like Transcription Factors - genetics
Male
Mice
Mice, Inbred C57BL
Promoter Regions, Genetic - genetics
Transcriptional Activation - genetics
Ubiquitin-Protein Ligases - genetics
ubiquitination
Ubiquitination - genetics
title Regulation of adipocyte differentiation by clusterin‐mediated Krüppel‐like factor 5 stabilization
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