1597-P: KCNH6 Regulates Hepatic Mitochondrial Function and Glucose Metabolism via NF-κB Pathway

KCN, a human ether-a-go-go-related gene, encodes KCN ion channel in the Kv11 family, which ranks 11th in abundance among different ion channel families. KCNH6, a subfamily of KCN potassium channel family, has been proven to affect glucose metabolism and insulin secretion both in humans and mice. However, the precise function of KCNH6 in the liver remains unknown. In this study, we showed that knockout (KO) of Kcnh6 impairs mitochondrial function and insulin tolerance as well as promotes high-fat-diet-induced insulin resistance. In line, overexpression of Kcnh6 in hepatocytes ameliorates fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes ameliorating insulin resistance. Similarly, induction of Kcnh6 by tail vein injection into KO mice decreased insulin tolerance. Mechanistically, Kcnh6 improved mitochondrial function and insulin secretion via the the NFκB-IκB kinase (IKK) pathway both in vitro and in vivo. Therefore, we suggest Kcnh6 as a potential novel therapeutic target to treat hepatic energy metabolism and mitochondrial dysfunction and insulin resistance.