Ubiquitin specific peptidase 1 promotes hepatic fibrosis through positive regulation of CXCL1 by deubiquitinating SNAIL

Du, Zhifeng; Wu, Tianchong; Liu, Linsen; Luo, Biwei; Wei, Cuifeng

doi:10.1016/j.dld.2021.02.025

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…To date, studies involving USP1 have been limited to the extent to which USP1 is important in promoting DNA damage repair in Fanconi anemia or regulating autophagy via ULK1 deubiqitination 25,26 . Although studies have shown that USP1 regulates hepatic brosis and glucose metabolism 12,27 , this is the rst study on USP1 in relation to adipogenesis. We con rmed that USP1 directly interacts with and deubiquitinates C/EBPβ, enhancing the stability of C/EBPβ in the regulation of adipogenesis.…”

Section: Discussionmentioning

confidence: 97%

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

Chun

Kim

Baek

et al. 2023

Preprint

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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 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.

show abstract

Section: Discussionmentioning

confidence: 97%

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

Chun

Kim

Baek

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Previously, we comprehensively analyzed the vital role of USP1 in HCC and identified it as a promising therapeutic target with good prognostic value [ 34 ]. After that, researchers focused more attention on the novel functions of USP1 in HCC and other liver diseases [ [35] , [36] , [37] , [38] , [39] ]. Recently, Du et al.…”

Section: Discussionmentioning

confidence: 99%

“…revealed that USP1 was also engaged in liver fibrosis. USP1 could significantly promote liver fibrosis via positive regulation of Snail-1 and CXCL1 [ 39 ]. These studies demonstrated that USP1 was a promising therapeutic target in various liver diseases.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of hepatocytes reveals the association between ubiquitin-specific peptidase 1 and yes-associated protein 1 during liver regeneration

Zhao

Zhang

et al. 2023

Regenerative Therapy

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“…To date, studies involving USP1 have been limited to the extent to which USP1 is important in promoting DNA damage repair in Fanconi anemia or regulating autophagy via ULK1 deubiqitination [ 32 , 33 ]. Although studies have shown that USP1 regulates hepatic fibrosis and glucose metabolism [ 23 , 34 ], this is the first study on USP1 in relation to adipogenesis. We confirmed that USP1 directly interacts with and deubiquitinates C/EBPβ, enhancing the stability of C/EBPβ in the regulation of adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

Kim,

Baek,

Lee

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

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.

show abstract

Ubiquitin specific peptidase 1 promotes hepatic fibrosis through positive regulation of CXCL1 by deubiquitinating SNAIL

Cited by 7 publications

References 30 publications

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

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

Transcriptomic analysis of hepatocytes reveals the association between ubiquitin-specific peptidase 1 and yes-associated protein 1 during liver regeneration

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

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