Hypoxia reduces HNF4α/MODY1 protein expression in pancreatic ß-cells by activating AMP-activated protein kinase.
J Biol Chem
; 292(21): 8716-8728, 2017 05 26.
Article
en En
| MEDLINE
| ID: mdl-28364040
ABSTRACT
Hypoxia plays a role in the deterioration of ß-cell function. Hepatocyte nuclear factor 4α (HNF4α) has an important role in pancreatic ß-cells, and mutations of the human HNF4A gene cause a type of maturity-onset diabetes of the young (MODY1). However, it remains unclear whether hypoxia affects the expression of HNF4α in ß-cells. Here, we report that hypoxia reduces HNF4α protein expression in ß-cells. Hypoxia-inducible factor was not involved in the down-regulation of HNF4α under hypoxic conditions. The down-regulation of HNF4α was dependent on the activation of AMP-activated protein kinase (AMPK), and the reduction of HNF4α protein expression by metformin, an AMPK activator, and hypoxia was inhibited by the overexpression of a kinase-dead (KD) form of AMPKα2. In addition, hypoxia decreased the stability of the HNF4α protein, and the down-regulation of HNF4α was sensitive to proteasome inhibitors. Adenovirus-mediated overexpression of KD-AMPKα2 improved insulin secretion in metformin-treated islets, hypoxic islets, and ob/ob mouse islets. These results suggest that down-regulation of HNF4α could be of importance in ß-cell dysfunction by hypoxia.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Regulación hacia Abajo
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Células Secretoras de Insulina
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Factor Nuclear 4 del Hepatocito
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Proteínas Quinasas Activadas por AMP
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2017
Tipo del documento:
Article