title: Hypoxia reduces HNF4α/MODY1 protein expression in pancreatic β-cells by activating AMP-activated protein kinase.
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 humanHNF4Agene 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, andob/obmouse islets. These results suggest that down-regulation of HNF4α could be of importance in β-cell dysfunction by hypoxia.
authors.affiliation: From the Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 and.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: From the Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 and.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tsuyama
authors.affiliation: From the Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 and.
authors.forename: Chinami
authors.initials: C
authors.lastname: Sato
authors.affiliation: From the Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 and.
authors.forename: Md Fazlul
authors.initials: MF
authors.lastname: Karim
authors.affiliation: From the Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 and.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshizawa
authors.affiliation: the Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: From the Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 and k-yamaga@kumamoto-u.ac.jp.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamagata
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D061988:Proteasome Inhibitors / Q000494:pharmacology
chemical_list: D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D007328:Insulin; D061988:Proteasome Inhibitors; D008687:Metformin; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated kinase (AMPK); hepatocyte nuclear factor 4 (HNF-4); hypoxia; transcription factor; β-cell (B-cell)