Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Beijing Sijiqing Hospital, Beijing, China.
Horm Metab Res. 2020 Sep;52(9):669-675. doi: 10.1055/a-1177-6814. Epub 2020 Aug 4.
Adult patients with a dysfunctional ether-a-go-go 2 (hERG2) protein, which is encoded by the gene present with hyperinsulinemia and hyperglycemia. However, the mechanism of in glucose metabolism disorders has not been clearly defined. It has been proposed that sustained endoplasmic reticulum (ER) stress is closely concerned with hepatic insulin resistance and inflammation. Here, we demonstrate that knockout (KO) mice had impaired glucose tolerance and increased levels of hepatic apoptosis, in addition to displaying an increased insulin resistance that was mediated by high ER stress levels. By contrast, overexpression of KCNH6 in primary hepatocytes led to a decrease in ER stress and apoptosis induced by thapsigargin. Similarly, induction of by tail vein injection into KO mice improved glucose tolerance by reducing ER stress and apoptosis. Furthermore, we show that KCNH6 alleviated hepatic ER stress, apoptosis, and inflammation via the NFκB-IκB kinase (IKK) pathway both in vitro and in vivo. In summary, our study provides new insights into the causes of ER stress and subsequent induction of primary hepatocytes apoptosis.
成年患者存在功能失调的醚-α--go-go 2（hERG2）蛋白，该蛋白由 基因编码，表现为高胰岛素血症和高血糖。然而， 在葡萄糖代谢紊乱中的机制尚未明确。有人提出，持续的内质网（ER）应激与肝胰岛素抵抗和炎症密切相关。在这里，我们证明 敲除（KO）小鼠的葡萄糖耐量受损，肝凋亡水平增加，同时表现出由高 ER 应激水平介导的胰岛素抵抗增加。相比之下，在原代肝细胞中过表达 KCNH6 会导致内质网应激和由 thapsigargin 诱导的细胞凋亡减少。同样，通过尾静脉注射将 诱导到 KO 小鼠中，通过减少 ER 应激和细胞凋亡来改善葡萄糖耐量。此外，我们还表明，KCNH6 通过体外和体内的 NFκB-IκB 激酶（IKK）途径减轻肝 ER 应激、细胞凋亡和炎症。总之，我们的研究为内质网应激和随后诱导原代肝细胞凋亡的原因提供了新的见解。
