1. Hypoxia reduces HNF4α/MODY1 protein expression in pancreatic β-cells by activating AMP-activated protein kinase
- Author
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Md. Fazlul Karim, Masahiro Inoue, Tatsuya Yoshizawa, Yoshifumi Sato, Tomonori Tsuyama, Chinami Sato, and Kazuya Yamagata
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Down-Regulation ,Mice, Obese ,AMP-Activated Protein Kinases ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,AMP-activated protein kinase ,Insulin-Secreting Cells ,Internal medicine ,Insulin Secretion ,medicine ,Animals ,Humans ,Insulin ,Protein kinase A ,Molecular Biology ,Transcription factor ,biology ,Activator (genetics) ,AMPK ,Molecular Bases of Disease ,Cell Biology ,Hypoxia (medical) ,Cell Hypoxia ,Metformin ,Hepatocyte nuclear factors ,030104 developmental biology ,Endocrinology ,Hepatocyte Nuclear Factor 4 ,Proteasome ,030220 oncology & carcinogenesis ,biology.protein ,medicine.symptom ,Proteasome Inhibitors - Abstract
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 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 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 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 β-cell dysfunction by hypoxia.
- Published
- 2017
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