Sato Yoshifumi, Tsuyama Tomonori, Sato Chinami, Karim Md Fazlul, Yoshizawa Tatsuya, Inoue Masahiro, Yamagata Kazuya
From the Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556 and.
the Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan.
J Biol Chem. 2017 May 26;292(21):8716-8728. doi: 10.1074/jbc.M116.767574. Epub 2017 Mar 31.
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 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 / mouse islets. These results suggest that down-regulation of HNF4α could be of importance in β-cell dysfunction by hypoxia.
缺氧在β细胞功能恶化中起作用。肝细胞核因子4α（HNF4α）在胰腺β细胞中具有重要作用，人类该基因的突变会导致一种青少年发病的成年型糖尿病（MODY1）。然而，尚不清楚缺氧是否会影响β细胞中HNF4α的表达。在此，我们报告缺氧会降低β细胞中HNF4α蛋白的表达。缺氧诱导因子不参与缺氧条件下HNF4α的下调。HNF4α的下调依赖于AMP激活的蛋白激酶（AMPK）的激活，并且二甲双胍（一种AMPK激活剂）和缺氧导致的HNF4α蛋白表达降低可被激酶失活（KD）形式的AMPKα2的过表达所抑制。此外，缺氧降低了HNF4α蛋白的稳定性，并且HNF4α的下调对蛋白酶体抑制剂敏感。腺病毒介导的KD-AMPKα2的过表达改善了二甲双胍处理的胰岛、缺氧胰岛和/小鼠胰岛中的胰岛素分泌。这些结果表明，HNF4α的下调在缺氧导致的β细胞功能障碍中可能具有重要意义。
