Horm Metab Res 2020; 52(09): 669-675
DOI: 10.1055/a-1177-6814
Endocrine Research

Effect of KCNH6 on Hepatic Endoplasmic Reticulum Stress and Glucose Metabolism

Jing Lu
1   Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
,
Han Shen
1   Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
2   Beijing Sijiqing Hospital, Beijing, China
,
Qi Li
1   Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
,
Feng-Ran Xiong
1   Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
,
Ming-Xia Yuan
1   Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
,
Jin-Kui Yang
1   Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
› Author Affiliations
Funding Information: This work was supported by grants from the National Natural Science Foundation of China (81800688) to J.L., and Beijing Municipal Administration of Hospitals Incubating Program (PX2019006) to J.L. and National Key R & D Program of China (2017YFC0909600) to J.K.Y.

Abstract

Adult patients with a dysfunctional ether-a-go-go 2 (hERG2) protein, which is encoded by the KCNH6 gene, present with hyperinsulinemia and hyperglycemia. However, the mechanism of KCNH6 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 Kcnh6 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 Kcnh6 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.

Supplementary Material



Publication History

Received: 09 October 2019

Accepted: 06 May 2020

Article published online:
04 August 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 
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