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1.
Cell Metab ; 33(6): 1171-1186.e9, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33951476

RESUMO

Antihyperglycemic therapy is an important priority for the treatment of type 2 diabetes (T2D). Excessive hepatic glucose production (HGP) is a major cause of fasting hyperglycemia. Therefore, a better understanding of its regulation would be important to develop effective antihyperglycemic therapies. Using a gluconeogenesis-targeted kinome screening approach combined with transcriptome analyses, we uncovered Nemo-like kinase (NLK) as a potent suppressor of HGP. Mechanistically, NLK phosphorylates and promotes nuclear export of CRTC2 and FOXO1, two key regulators of hepatic gluconeogenesis, resulting in the proteasome-dependent degradation of the former and the inhibition of the self-transcriptional activity and expression of the latter. Importantly, the expression of NLK is downregulated in the liver of individuals with diabetes and in diabetic rodent models and restoring NLK expression in the mouse model ameliorates hyperglycemia. Therefore, our findings uncover NLK as a critical player in the gluconeogenic regulatory network and as a potential therapeutic target for T2D.

2.
Hypertension ; 76(4): 1219-1230, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32862709

RESUMO

Pathological cardiac hypertrophy is one of the major predictors and inducers of heart failure, the end stage of various cardiovascular diseases. However, the molecular mechanisms underlying pathogenesis of pathological cardiac hypertrophy remain largely unknown. Here, we provided the first evidence that STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) is a key negative regulator of this disease. We found that the expression of STEAP3 was reduced in pressure overload-induced hypertrophic hearts and phenylephrine-induced hypertrophic cardiomyocytes. In a transverse aortic constriction-triggered mouse cardiac hypertrophy model, STEAP3 deficiency remarkably deteriorated cardiac hypertrophy and fibrosis, whereas the opposite phenotype was observed in the cardiomyocyte-specific STEAP3 overexpressing mice. Accordingly, STEAP3 significantly mitigated phenylephrine-induced cell enlargement in primary neonatal rat cardiomyocytes. Mechanistically, via RNA-seq and immunoprecipitation-mass screening, we demonstrated that STEAP3 directly bond to Rho family small GTPase 1 and suppressed the activation of downstream mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade. Remarkably, the antihypertrophic effect of STEAP3 was largely blocked by overexpression of constitutively active mutant Rac1 (G12V). Our study indicates that STEAP3 serves as a novel negative regulator of pathological cardiac hypertrophy by blocking the activation of the Rac1-dependent signaling cascade and may contribute to exploring effective therapeutic strategies of pathological cardiac hypertrophy treatment.


Assuntos
Cardiomegalia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Oxirredutases/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , Oxirredutases/genética , Ratos
3.
Hepatology ; 71(1): 93-111, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31222801

RESUMO

Activation of apoptosis signal-regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte-derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes lysine 6 (Lys6)-linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet-induced liver inflammation and fibrosis were substantially attenuated in Traf6+/- mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6-linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N-terminal dimerization of ASK1, resulting in the boosted activation of ASK1-c-Jun N-terminal kinase 1/2 (JNK1/2)-mitogen-activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6-linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6-linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.


Assuntos
Apoptose , Hepatite/etiologia , Hepatócitos , Cirrose Hepática/etiologia , MAP Quinase Quinase Quinase 5/metabolismo , Fator 6 Associado a Receptor de TNF/fisiologia , Ubiquitinação , Animais , Lisina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Índice de Gravidade de Doença
4.
Artif Cells Nanomed Biotechnol ; 46(sup3): S133-S137, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30618312

RESUMO

The development of hemoglobin-based oxygen carriers (HBOCs) is a persistent and urgent need in biomedicine. As a potential HBOCs, Dextran-hemoglobin (Dex-bHb) has been developed over the past years. The novel Dex-bHb, whose thiol group of Cys-93(ß) was reversibly protected, was produced and the characteristics were evaluated in our previous study. Herein, blood compatibility was characterized in terms of the red blood cell aggregation and hemolysis rate in vitro, and Dex-bHb showed no obvious effects. After intravenous administration of Dex-bHb to golden Syrian hamsters with hemorrhages shock, it showed mean arterial pressure recovery, blood flow increase and the organ protection from serious hemorrhage injury. Consequently, Dex-bHb is hopeful to be a safe and available blood substitute.


Assuntos
Substitutos Sanguíneos/farmacologia , Dextranos/farmacologia , Hemoglobinas/farmacologia , Oxigênio/sangue , Choque Hemorrágico/sangue , Choque Hemorrágico/tratamento farmacológico , Animais , Bovinos , Masculino , Mesocricetus , Choque Hemorrágico/patologia
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