The case for FAT10 as a novel target in fatty liver diseases

Wimalarathne, Madushika; Wilkerson-Vidal, Quiana C.; Hunt, Emily C.; Love‐Rutledge, Sharifa

doi:10.3389/fphar.2022.972320

Cited by 5 publications

(4 citation statements)

References 110 publications

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“…Neddylation is regulated by NEDD8 and the next enzymatic cascade response of E1(NAE1), E2 (UBC12), and E3 (Cullin-RING ligases); it causes oncogenic modifications by degrading the tumor suppressor proteins [ 23 ]. FAT10 is another Ubl used to modulate substrate degradation by directly binding to substrates; subsequently, FAT10 and its substrates degrade together [ 24 ]. Interferon-stimulating gene 15 (ISG15) not only acts as a cytokine induced by viral infection, but also as a ubiquitin molecule [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

The Ubiquitin–Proteasome System in Tumor Metabolism

Wang

Xiang

Fan

et al. 2023

Cancers

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Metabolic reprogramming, which is considered a hallmark of cancer, can maintain the homeostasis of the tumor environment and promote the proliferation, survival, and metastasis of cancer cells. For instance, increased glucose uptake and high glucose consumption, known as the “Warburg effect,” play an essential part in tumor metabolic reprogramming. In addition, fatty acids are harnessed to satisfy the increased requirement for the phospholipid components of biological membranes and energy. Moreover, the anabolism/catabolism of amino acids, such as glutamine, cystine, and serine, provides nitrogen donors for biosynthesis processes, development of the tumor inflammatory environment, and signal transduction. The ubiquitin–proteasome system (UPS) has been widely reported to be involved in various cellular biological activities. A potential role of UPS in the metabolic regulation of tumor cells has also been reported, but the specific regulatory mechanism has not been elucidated. Here, we review the role of ubiquitination and deubiquitination modification on major metabolic enzymes and important signaling pathways in tumor metabolism to inspire new strategies for the clinical treatment of cancer.

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Section: Introductionmentioning

confidence: 99%

The Ubiquitin–Proteasome System in Tumor Metabolism

Wang

Xiang

Fan

et al. 2023

Cancers

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“…Besides Ubd directly targets its substrate for degradation by the 26S proteasome ( 32 ). Although Ubd is a gene responsive to stress and inflammation ( 33 ) and is already thought to play a role in inflammation driven diseases ( 34 ), we cannot draw a conclusion that any gene responsive to stress and inflammation is a candidate for insulin resistance. By our validation experiment, either overexpression or knockdown, we clarified the direct negative correlation between UBD expression and p-akt level, a major insulin resistance index.…”

Section: Discussionmentioning

confidence: 96%

The identification of a novel shared therapeutic target and drug across all insulin-sensitive tissues under insulin resistance

Xu,

Zhu,

et al. 2024

Front. Nutr.

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BackgroundTo identify key and shared insulin resistance (IR) molecular signatures across all insulin-sensitive tissues (ISTs), and their potential targeted drugs.MethodsThree datasets from Gene Expression Omnibus (GEO) were acquired, in which the ISTs (fat, muscle, and liver) were from the same individual with obese mice. Integrated bioinformatics analysis was performed to obtain the differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was carried out to determine the “most significant trait-related genes” (MSTRGs). Enrichment analysis and PPI network were performed to find common features and novel hub genes in ISTs. The shared genes of DEGs and genes between DEGs and MSTRGs across four ISTs were identified as key IR therapeutic target. The Attie Lab diabetes database and obese rats were used to verify candidate genes. A medical drug-gene interaction network was conducted by using the Comparative Toxicogenomics Database (CTD) to find potential targeted drugs. The candidate drug was validated in Hepa1-6 cells.ResultsLipid metabolic process, mitochondrion, and oxidoreductase activity as common features were enriched from ISTs under an obese context. Thirteen shared genes (Ubd, Lbp, Hp, Arntl, Cfd, Npas2, Thrsp., Tpx2, Pkp1, Sftpd, Mthfd2, Tnfaip2, and Vnn3) of DEGs across ISTs were obtained and confirmed. Among them, Ubd was the only shared gene between DEGs and MSTRGs across four ISTs. The expression of Ubd was significantly upregulated across four ISTs in obese rats, especially in the liver. The IR Hepa1-6 cell models treated with dexamethasone (Dex), palmitic acid (PA), and 2-deoxy-D-ribose (dRib) had elevated expression of Ubd. Knockdown of Ubd increased the level of p-Akt. A lowing Ubd expression drug, promethazine (PMZ) from CTD analysis rescued the decreased p-Akt level in IR Hepa1-6 cells.ConclusionThis study revealed Ubd, a novel and shared IR molecular signature across four ISTs, as an effective biomarker and provided new insight into the mechanisms of IR. PMZ was a candidate drug for IR which increased p-Akt level and thus improved IR by targeting Ubd and downregulation of Ubd expression. Both Ubd and PMZ merit further clinical translational investigation to improve IR.

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“…More recently, a ubiquitin-like protein that targets proteins for degradation by being part of the ubiquitin-proteasome system (UPS), and thus affecting the peptide/HLA-I presentation, has been reported adjacent to the HLA-F gene region. This protein was called human leukocyte antigen F locus adjacent transcript 10 (FAT10), and has been associated with a susceptibility to inflammation-driven diseases, like nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and HCC [ 145 ]. Inflammatory stimuli, fibrogenesis and cytokines induced the expression of FAT10 [ 50 , 145 , 146 , 147 ].…”

Section: Non-classical Hla Class I Molecules (Hla-ib)mentioning

confidence: 99%

“…This protein was called human leukocyte antigen F locus adjacent transcript 10 (FAT10), and has been associated with a susceptibility to inflammation-driven diseases, like nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and HCC [ 145 ]. Inflammatory stimuli, fibrogenesis and cytokines induced the expression of FAT10 [ 50 , 145 , 146 , 147 ]. FAT10 has been involved in the Mallory–Denk Bodies (MDBs), aggresomal molecules formed from undigested ubiquitinated short-lived proteins resulting from a reduced proteasome’s degradation rate, observed in hepatitis, alcoholic steatohepatitis, NAH and HCC [ 146 , 148 , 149 , 150 , 151 ].…”

Section: Non-classical Hla Class I Molecules (Hla-ib)mentioning

confidence: 99%

Non-Classical HLA Class 1b and Hepatocellular Carcinoma

Tornesello

Racanelli

et al. 2023

Biomedicines

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A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host’s defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.

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The case for FAT10 as a novel target in fatty liver diseases

Cited by 5 publications

References 110 publications

The Ubiquitin–Proteasome System in Tumor Metabolism

The Ubiquitin–Proteasome System in Tumor Metabolism

The identification of a novel shared therapeutic target and drug across all insulin-sensitive tissues under insulin resistance

Non-Classical HLA Class 1b and Hepatocellular Carcinoma

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