A kinome screen reveals that Nemo-like kinase is a key suppressor of hepatic gluconeogenesis.
Cell Metab
; 33(6): 1171-1186.e9, 2021 06 01.
Article
em En
| MEDLINE
| ID: mdl-33951476
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Peptídeos e Proteínas de Sinalização Intracelular
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Diabetes Mellitus Tipo 2
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Quinase I-kappa B
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Proteína Forkhead Box O1
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Metab
Ano de publicação:
2021
Tipo de documento:
Article