Herpesvirus-associated Ubiquitin-specific Protease (HAUSP) Modulates Peroxisome Proliferator-activated Receptor γ (PPARγ) Stability through Its Deubiquitinating Activity

Lee, Kyeong Won; Cho, Jin Gu; Kim, Chul Min; Kang, Aram; Kim, Min; Ahn, Byung Yong; Chung, Sung Soo; Lim, Key Hwan; Baek, Kwang‐Hyun; Sung, Jong Hwan; Park, Kyong Soo; Park, Sang Gyu

doi:10.1074/jbc.m113.496331

Cited by 21 publications

(21 citation statements)

References 50 publications

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“…Inhibition of proteasome activity by proteasome inhibitors increases PPARγ stability, suggesting ubiquitin modification of PPARγ is an important determinant of PPARγ activity 58 . Several ubiquitin ligases, such as FBOX9 and Cul4B, and an ubiquitin-specific protease (HAUSP) targeting PPARγ have been identified, and an increase in PPARγ stability generally promotes PPARγ activity and adipogenesis 59 – 61 . Interestingly, PPARγ agonists, TZDs, stimulate the ubiquitination of PPARγ, which can be mediated by an ubiquitin ligase, Siah1 58 , 62 .…”

Section: Regulation Of Pparγ By Ptms To Reduce the Side Effects Of Tzmentioning

confidence: 99%

Re-highlighting the action of PPARγ in treating metabolic diseases

2018

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Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family and plays an important role in adipocyte differentiation, glucose homeostasis, and insulin sensitivity. Thiazolidinediones (TZDs), synthetic ligands of PPARγ, have been used for the treatment of diabetes mellitus for two decades. TZDs were expected to be amazing drugs not only for type 2 diabetes but also for metabolic syndrome and atherosclerotic vascular disease because they can reduce both insulin resistance and inflammation in experimental studies. However, serious unwanted effects pushed TZDs back to an optional second-tier drug for type 2 diabetes. Nevertheless, PPARγ is still one of the most important targets for the treatment of insulin resistance and diabetes mellitus, and novel strategies to modulate PPARγ activity to enhance its beneficial effects and reduce unwanted adverse effects are anticipated. Recent studies showed that post-translational modification (PTM) of PPARγ regulates PPARγ activity or stability and may be a novel way to optimize PPARγ activity with reduced adverse effects. In this review, we will focus on recent advances in PTM of PPARγ and the mechanisms regulating PPARγ function as well as in the development of PPARγ modulators or agonists.

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Section: Regulation Of Pparγ By Ptms To Reduce the Side Effects Of Tzmentioning

confidence: 99%

Re-highlighting the action of PPARγ in treating metabolic diseases

2018

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“…HEK293, C2C12, and 3T3-L1 cells were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 10% FBS and 1% penicillin and streptomycin. Adipocyte differentiation was induced as previously described 45 . C2C12 cells were differentiated as previously described 46 .…”

Section: Methodsmentioning

confidence: 99%

MD001, a Novel Peroxisome Proliferator-activated Receptor α/γ Agonist, Improves Glucose and Lipid Metabolism

Kim

Hong

Park

et al. 2019

Sci Rep

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Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to treat metabolic diseases; however, most of them exhibit side effects such as body weight gain and oedema. Therefore, we developed a novel PPARα/γ dual agonist that modulates glucose and lipid metabolism without adverse effects. We synthesised novel compounds composed of coumarine and chalcone, determined their crystal structures, and then examined their binding affinity toward PPARα/γ. We investigated the expression of PPARα and PPARγ target genes by chemicals in HepG2, differentiated 3T3-L1, and C2C12 cells. We examined the effect of chemicals on glucose and lipid metabolism in db/db mice. Only MD001 functions as a PPARα/γ dual agonist in vitro. MD001 increased the transcriptional activity of PPARα and PPARγ, resulting in enhanced expression of genes related to β-oxidation and fatty acid and glucose uptake. MD001 significantly improved blood metabolic parameters, including triglycerides, free fatty acids, and glucose, in db/db mice. In addition, MD001 ameliorated hepatic steatosis by stimulating β-oxidation in vitro and in vivo. Our results demonstrated the beneficial effects of the novel compound MD001 on glucose and lipid metabolism as a PPARα/γ dual agonist. Consequently, MD001 may show potential as a novel drug candidate for the treatment of metabolic disorders.

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“…Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is stabilized by HAUSP and plays a central role in adipogenesis, glucose homeostasis, lipid metabolism, and osteogenesis. 54 Fine-tuning of nuclear forkhead box protein O1 (FoxO1) by HAUSP-mediated deubiquitination is also important in maintaining hepatic glucose levels. Given that these molecules are crucial regulators of functions in other metabolic tissues, such as in skeletal muscles and adipose tissues, these findings demonstrate the involvement of HAUSP in diabetes and other metabolic disorders, which makes it a suitable candidate to be targeted in the context of these diseases.…”

Section: Hausp—physiology and Disease Contextmentioning

confidence: 99%

“…92 Host-virus interactions, inflammation, immune functions, and cancer signaling Viral infection and associated cancers—Burkitt’s lymphoma, Hodgkin’s lymphoma, HSV-1 infection, Kaposi’s sarcoma, nasopharyngeal carcinoma, etc. PPAR-γ, 54 FOXO1. 55 Regulation of adipogenesis, osteogenesis, glucose and lipid metabolism Metabolic disorders and diabetes Ci/Gli, 90 REST.…”

Section: Role Of Hausp In Multiple Cellular Eventsmentioning

confidence: 99%

Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases

Bhattacharya

Chakraborty

Basu³

et al. 2018

Sig Transduct Target Ther

117

129

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Herpesvirus-associated ubiquitin-specific protease (HAUSP) is a USP family deubiquitinase. HAUSP is a protein of immense biological importance as it is involved in several cellular processes, including host-virus interactions, oncogenesis and tumor suppression, DNA damage and repair processes, DNA dynamics and epigenetic modulations, regulation of gene expression and protein function, spatio-temporal distribution, and immune functions. Since its discovery in the late 1990s as a protein interacting with a herpes virus regulatory protein, extensive studies have assessed its complex roles in p53-MDM2-related networks, identified numerous additional interacting partners, and elucidated the different roles of HAUSP in the context of cancer, development, and metabolic and neurological pathologies. Recent analyses have provided new insights into its biochemical and functional dynamics. In this review, we provide a comprehensive account of our current knowledge about emerging insights into HAUSP in physiology and diseases, which shed light on fundamental biological questions and promise to provide a potential target for therapeutic intervention.

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Herpesvirus-associated Ubiquitin-specific Protease (HAUSP) Modulates Peroxisome Proliferator-activated Receptor γ (PPARγ) Stability through Its Deubiquitinating Activity

Cited by 21 publications

References 50 publications

Re-highlighting the action of PPARγ in treating metabolic diseases

Re-highlighting the action of PPARγ in treating metabolic diseases

MD001, a Novel Peroxisome Proliferator-activated Receptor α/γ Agonist, Improves Glucose and Lipid Metabolism

Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases

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