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Hypoxia reduces HNF4?/MODY1 protein expression in pancreatic ?-cells by activating AMP-activated protein kinase.


ABSTRACT: Hypoxia plays a role in the deterioration of ?-cell function. Hepatocyte nuclear factor 4? (HNF4?) has an important role in pancreatic ?-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 HNF4? in ?-cells. Here, we report that hypoxia reduces HNF4? protein expression in ?-cells. Hypoxia-inducible factor was not involved in the down-regulation of HNF4? under hypoxic conditions. The down-regulation of HNF4? was dependent on the activation of AMP-activated protein kinase (AMPK), and the reduction of HNF4? protein expression by metformin, an AMPK activator, and hypoxia was inhibited by the overexpression of a kinase-dead (KD) form of AMPK?2. In addition, hypoxia decreased the stability of the HNF4? protein, and the down-regulation of HNF4? was sensitive to proteasome inhibitors. Adenovirus-mediated overexpression of KD-AMPK?2 improved insulin secretion in metformin-treated islets, hypoxic islets, and ob/ob mouse islets. These results suggest that down-regulation of HNF4? could be of importance in ?-cell dysfunction by hypoxia.

SUBMITTER: Sato Y 

PROVIDER: S-EPMC5448099 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Hypoxia reduces HNF4α/MODY1 protein expression in pancreatic β-cells by activating AMP-activated protein kinase.

Sato Yoshifumi Y   Tsuyama Tomonori T   Sato Chinami C   Karim Md Fazlul MF   Yoshizawa Tatsuya T   Inoue Masahiro M   Yamagata Kazuya K  

The Journal of biological chemistry 20170331 21


Hypoxia plays a role in the deterioration of β-cell function. Hepatocyte nuclear factor 4α (HNF4α) has an important role in pancreatic β-cells, and mutations of the human <i>HNF4A</i> gene cause a type of maturity-onset diabetes of the young (MODY1). However, it remains unclear whether hypoxia affects the expression of HNF4α in β-cells. Here, we report that hypoxia reduces HNF4α protein expression in β-cells. Hypoxia-inducible factor was not involved in the down-regulation of HNF4α under hypoxic  ...[more]

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