Association of polymorphisms in &lt;i&gt;GCKR&lt;/i&gt; and &lt;i&gt;TRIB1&lt;/i&gt; with nonalcoholic fatty liver disease and metabolic syndrome traits

Kitamoto, Aya; Kitamoto, Takuya; Nakamura, Takahiro; Ogawa, Yasuhiro; Yoneda, Masato; Hyogo, Hideyuki; Ochi, Hidenori; Mizusawa, Seiho; Ueno, Takato; Nakao, Kazuwa; Sekine, Akihiro; Chayama, Kazuaki; Nakajima, Atsushi; Hotta, Kikuko

doi:10.1507/endocrj.ej14-0052

Cited by 69 publications

(81 citation statements)

References 31 publications

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“…Our study selected 182 NAFLD patients and 195 healthy controls to observe the correlation between NCAN rs2228603 and NAFLD. We found no carriers with TT genotype both in NAFLD and control group, also no significant association of NCAN rs2228603 with NAFLD was observed in our subjects, which latter was consistent with some previous findings [32, 34, 35]. While Speliotes et al identified that variant in the gene NCAN was strongly associated with histologic NAFLD and increasing computed tomography (CT) hepatic steatosis [14].…”

Section: Discussionsupporting

confidence: 92%

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Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study

Yuan

Lu³

et al. 2016

Lipids Health Dis

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BackgroundRecently genome-wide association studies identified that NCAN rs2228603 polymorphism was associated with non-alcoholic fatty liver disease (NAFLD) mainly in subjects of European ancestry. While no research have been conducted to demonstrate the relationship between NCAN rs2228603 and NAFLD in Chinese Han adults. The aim of this study was to investigate whether NCAN rs2228603 is associated with NAFLD in Chinese population.MethodsGene NCAN rs2228603 was genotyped in 182 patients with NAFLD and 195 healthy controls. The expression of NCAN was tested according to polymerase chain reaction analysis (PCR) and serum lipids were performed by biology techniques.ResultsNo significant difference was found in genotype and allele frequencies of NCAN rs2228603 between the NAFLD group and the controls (P > 0.05). Subjects with the NCAN rs2228603 CT genotype showed a higher level of alkaline phosphatase (AKP) (P = 0.017) and a higher high-density lipoprotein (HDL) (P < 0.05).ConclusionsOur study for the first time identified that the gene NCAN rs2228603 is not a risk factor for the incidence of NAFLD in Chinese population. Also we found the dual and opposite role of T variant in protecting liver with a higher level of HDL and conferring risk for liver damage with a higher level of AKP.Trial registrationChinese Clinical Trial Register.gov Identifier: ChiCTR-ROC-15006447.

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Section: Discussionsupporting

confidence: 92%

“…Recently the gene NCAN on NAFLD has been studied, however, the results were controversial [23, 34]. The present study firstly evaluated the association between rs2228603 polymorphism in the gene NCAN and NAFLD in Chinese population.…”

Section: Discussionmentioning

confidence: 97%

Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study

Yuan

Lu³

et al. 2016

Lipids Health Dis

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“…Based on the crystal structures of PKA and TRIB1, we speculate that this mutation contributes to abnormal TRIB1 pseudokinase function by disrupting regulatory protein interactions with interacting partners, such as MAPKK family members [46], Ubiquitin E3 ligases, or cis -acting flanking regulatory segments in TRIB itself. Of related interest, TRIB1 gene polymorphisms are also associated with nonalcoholic liver and metabolic syndromes [63], consistent with a relatively specialized function for TRIB1 in lipid metabolism 8, 43.…”

Section: Tribbles Links To Cancer: a Corruption Of Cell Signaling?mentioning

confidence: 88%

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Eyers

Keeshan

Kannan

2017

Trends in Cell Biology

190

207

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The Tribbles (TRIB) pseudokinases control multiple aspects of eukaryotic cell biology and evolved unique features distinguishing them from all other protein kinases. The atypical pseudokinase domain retains a regulated binding platform for substrates, which are ubiquitinated by context-specific E3 ligases. This plastic configuration has also been exploited as a scaffold to support the modulation of canonical MAPK and AKT modules. In this review, we discuss the evolution of TRIBs and their roles in vertebrate cell biology. TRIB2 is the most ancestral member of the family, whereas the emergence of TRIB3 homologs in mammals supports additional biological roles, many of which are currently being dissected. Given their pleiotropic role in diseases, the unusual TRIB pseudokinase conformation provides a highly attractive opportunity for drug design.

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“…Similar to TRB2, TRB1 is involved in AML progression, and drives C/EBPα degradation in leukaemia cells [95,96]. TRB1 also regulates the development of (non-alcoholic) fatty liver disease [98]. Interestingly, overexpression of the R107L cancer-associated mutant increases the degradation of C/EBPα to a greater extent than that of WT TRB1, although the mechanism remains obscure.…”

Section: Tribbles Pseudokinasesmentioning

confidence: 99%

Going for broke: targeting the human cancer pseudokinome

Bailey

Byrne

McSkimming

et al. 2015

Biochemical Journal

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Protein phosphorylation lies at the heart of cell signalling, and somatic mutation(s) in kinases drives and sustains a multitude of human diseases, including cancer. The human protein kinase superfamily (the kinome) encodes approximately 50 'pseudokinases', which were initially predicted to be incapable of dynamic cell signalling when compared with canonical enzymatically active kinases. This assumption was supported by bioinformatics, which showed that amino acid changes at one or more key loci, making up the nucleotide-binding site or phosphotransferase machinery, were conserved in multiple vertebrate and non-vertebrate pseudokinase homologues. Protein kinases are highly attractive targets for drug discovery, as evidenced by the approval of almost 30 kinase inhibitors in oncology, and the successful development of the dual JAK1/2 (Janus kinase 1/2) inhibitor ruxolitinib for inflammatory indications. However, for such a large (>550) protein family, a remarkable number have still not been analysed at the molecular level, and only a surprisingly small percentage of kinases have been successfully targeted clinically. This is despite evidence that many are potential candidates for the development of new therapeutics. Indeed, several recent reports confirm that disease-associated pseudokinases can bind to nucleotide co-factors at concentrations achievable in the cell. Together, these findings suggest that drug targeting using either ATP-site or unbiased ligand-discovery approaches should now be attempted using the validation technology currently employed to evaluate their classic protein kinase counterparts. In the present review, we discuss members of the human pseudokinome repertoire, and catalogue somatic amino acid pseudokinase mutations that are emerging as the depth and clinical coverage of the human cancer pseudokinome expand.

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Association of polymorphisms in <i>GCKR</i> and <i>TRIB1</i> with nonalcoholic fatty liver disease and metabolic syndrome traits

Cited by 69 publications

References 31 publications

Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study

Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

Going for broke: targeting the human cancer pseudokinome

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