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1.
Nat Metab ; 6(1): 94-112, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38216738

RESUMO

Adipose tissue lipolysis is mediated by cAMP-protein kinase A (PKA)-dependent intracellular signalling. Here, we show that PKA targets p21-activated kinase 4 (PAK4), leading to its protein degradation. Adipose tissue-specific overexpression of PAK4 in mice attenuates lipolysis and exacerbates diet-induced obesity. Conversely, adipose tissue-specific knockout of Pak4 or the administration of a PAK4 inhibitor in mice ameliorates diet-induced obesity and insulin resistance while enhancing lipolysis. Pak4 knockout also increases energy expenditure and adipose tissue browning activity. Mechanistically, PAK4 directly phosphorylates fatty acid-binding protein 4 (FABP4) at T126 and hormone-sensitive lipase (HSL) at S565, impairing their interaction and thereby inhibiting lipolysis. Levels of PAK4 and the phosphorylation of FABP4-T126 and HSL-S565 are enhanced in the visceral fat of individuals with obesity compared to their lean counterparts. In summary, we have uncovered an important role for FABP4 phosphorylation in regulating adipose tissue lipolysis, and PAK4 inhibition may offer a therapeutic strategy for the treatment of obesity.


Assuntos
Lipólise , Esterol Esterase , Animais , Camundongos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Lipólise/fisiologia , Obesidade/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Esterol Esterase/genética , Esterol Esterase/metabolismo
3.
Nat Commun ; 14(1): 4987, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37591884

RESUMO

PPARα corepressor NCoR1 is a key regulator of fatty acid ß-oxidation and ketogenesis. However, its regulatory mechanism is largely unknown. Here, we report that oncoprotein p21-activated kinase 4 (PAK4) is an NCoR1 kinase. Specifically, PAK4 phosphorylates NCoR1 at T1619/T2124, resulting in an increase in its nuclear localization and interaction with PPARα, thereby repressing the transcriptional activity of PPARα. We observe impaired ketogenesis and increases in PAK4 protein and NCoR1 phosphorylation levels in liver tissues of high fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients. Forced overexpression of PAK4 in mice represses ketogenesis and thereby increases hepatic fat accumulation, whereas genetic ablation or pharmacological inhibition of PAK4 exhibites an opposite phenotype. Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid ß-oxidation and ketogenesis.


Assuntos
Ácidos Graxos , PPAR alfa , Quinases Ativadas por p21 , Animais , Camundongos , Proteínas Correpressoras , Ácidos Graxos/metabolismo , Quinases Ativadas por p21/genética , PPAR alfa/genética , Correpressor 1 de Receptor Nuclear/genética , Humanos , Fosforilação , Transdução de Sinais
4.
Int J Mol Sci ; 24(12)2023 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-37372931

RESUMO

Sepsis-induced acute kidney injury (AKI) is a common complication in critically ill patients, often resulting in high rates of morbidity and mortality. Previous studies have demonstrated the effectiveness of casein kinase 2 alpha (CK2α) inhibition in ameliorating ischemia-reperfusion-induced AKI. In this study, our aim was to investigate the potential of the selective CK2α inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBBt), in the context of sepsis-induced AKI. To assess this, we initially confirmed an upregulation of CK2α expression following a cecum ligation and puncture (CLP) procedure in mice. Subsequently, TBBt was administered to a group of mice prior to CLP, and their outcomes were compared to those of sham mice. The results revealed that, following CLP, the mice exhibited typical sepsis-associated patterns of AKI, characterized by reduced renal function (evidenced by elevated blood urea nitrogen and creatinine levels), renal damage, and inflammation (indicated by increased tubular injury score, pro-inflammatory cytokine levels, and apoptosis index). However, mice treated with TBBt demonstrated fewer of these changes, and their renal function and architecture remained comparable to that of the sham mice. The anti-inflammatory and anti-apoptotic properties of TBBt are believed to be associated with the inactivation of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. In conclusion, these findings suggest that inhibiting CK2α could be a promising therapeutic strategy for treating sepsis-induced AKI.


Assuntos
Injúria Renal Aguda , Caseína Quinase II , Inibidores de Proteínas Quinases , Sepse , Triazóis , Caseína Quinase II/antagonistas & inibidores , Sepse/complicações , Injúria Renal Aguda/microbiologia , Injúria Renal Aguda/prevenção & controle , Triazóis/farmacologia , Triazóis/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Masculino
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