Effect of KCNH6 on Hepatic Endoplasmic Reticulum Stress and Glucose Metabolism

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.

KCNH6 Enhanced Hepatic Glucose Metabolism through Mitochondrial Ca2+ Regulation and Oxidative Stress Inhibition

“…Our group found that adult patients or mice with dysfunctional KCNH6 gene expression presented with hypoinsulinemia or hyperglycemia [ 12 , 13 ]. Another study revealed that KCNH6 may cause endoplasmic reticulum (ER) stress in the liver and cell apoptosis [ 14 ].…”