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Deubiquitinase USP1 enhances CCAAT/enhancer-binding protein beta (C/EBPβ) stability and accelerates adipogenesis and lipid accumulation

 Myung Sup Kim  ;  Jung-Hwan Baek  ;  JinAh Lee  ;  Aneesh Sivaraman  ;  Kyeong Lee  ;  Kyung-Hee Chun 
 CELL DEATH & DISEASE, Vol.14(11) : 776, 2023-11 
Journal Title
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3T3-L1 Cells ; Adipogenesis* / genetics ; Animals ; CCAAT-Enhancer-Binding Protein-beta* / genetics ; CCAAT-Enhancer-Binding Protein-beta* / metabolism ; Deubiquitinating Enzymes ; Diet, High-Fat ; Metabolic Diseases* ; Mice ; PPAR gamma / metabolism ; Triglycerides ; Ubiquitin-Specific Proteases* / genetics
Dysregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of several metabolic disorders, including obesity, diabetes, and non-alcoholic fatty liver disease; however, the mechanisms controlling pathogenic metabolic disorders remain unclear. Transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) regulates adipogenic genes. The study showed that the expression level of C/EBPβ is post-translationally regulated by the deubiquitinase ubiquitin-specific protease 1 (USP1) and that USP1 expression is remarkably upregulated during adipocyte differentiation and in the adipose tissue of mice fed a high-fat diet (HFD). We found that USP1 directly interacts with C/EBPβ. Knock-down of USP1 decreased C/EBPβ protein stability and increased its ubiquitination. Overexpression of USP1 regulates its protein stability and ubiquitination, whereas catalytic mutant of USP1 had no effect on them. It suggests that USP1 directly deubiquitinases C/EBPβ and increases the protein expression, leading to adipogenesis and lipid accumulation. Notably, the USP1-specific inhibitor ML323-originally developed to sensitize cancer cells to DNA-damaging agents-decreased adipocyte differentiation and lipid accumulation in 3T3-L1 cells without cytotoxicity. Oral gavage of ML323 was administered to HFD-fed mice, which showed weight loss and improvement in insulin and glucose sensitivity. Both fat mass and adipocyte size in white adipose tissues were significantly reduced by ML323 treatment, which also reduced the expression of genes involved in adipogenesis and inflammatory responses. ML323 also reduced lipid accumulation, hepatic triglycerides, free fatty acids, and macrophage infiltration in the livers of HFD-fed mice. Taken together, we suggest that USP1 plays an important role in adipogenesis by regulating C/EBPβ ubiquitination, and USP1-specific inhibitor ML323 is a potential treatment option and further study by ML323 is needed for clinical application for metabolic disorders.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myung Sup(김명섭)
Baek, Jung Hwan(백정환) ORCID logo https://orcid.org/0000-0002-2250-1557
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
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