Diabetes, obesity & metabolism · 2026
KCNH6 Controls Hepatic Lipid Metabolism by Regulating Mitochondrial Function Associated With IKKβ/NF-κB Activation.
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Zhao Ru-Xuan, Lu Jing, Xiong Feng-Ran, Wang Yuan, Zhang Chen-Yang, Wei Gang, Zhang Qian-Rui, Yang Jin-Kui
Аннотация
AIM: Fatty liver diseases are severe and increasingly global pandemic resulted from metabolic diseases including metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM). Mitochondrial function is a critical factor in the pathogenesis and advancement of these diseases. Our previous results revealed that KCNH6 gene is associated with hyperinsulinemia and hyperglycemia in both humans and mice. In this study, we aim to detect the precise function of KCNH6 in hepatic lipid metabolism.
MATERIALS AND METHODS: We used whole-body Kcnh6 knockout (KO) mice as model mice and fed the mice a standard chow diet (SD) and/or high-fat diet (HFD) to evaluate the responsiveness of the liver. Glucose and lipid metabolisms were detected in mice. Genes participating in cholesterol biosynthesis and fatty acid β-oxidation pathways were also evaluated using Western blot and qPCR experiments. Metabolic cage and seahorse metabolic flux were conducted to confirm mitochondrial function.
RESULTS: KCNH6 knockout impaired glucose metabolism through the AKT pathway. KCNH6 deficiency caused increased obesity and aggravated insulin resistance. KO mice exhibited aggravated HFD-induced hepatic steatosis, which was associated with dysregulation of the ACCα signaling pathway. Genetic ablation of KCNH6 resulted in altered expression profiles of genes participating in cholesterol biosynthesis and fatty acid β-oxidation pathways. KCNH6 knockout also altered cholesterol synthesis and β-oxidation of fatty acids. In addition, KCNH6 loss impaired energy metabolism and mitochondrial function. Mechanistically, KCNH6 knockout increased inflammation via NF-κB signaling pathway through interaction with IKKβ directly.
CONCLUSIONS: In conclusion, our data showed that KCNH6 exerts an important role in the regulation of hepatic lipid metabolism through mitochondrial functional pathways.
MATERIALS AND METHODS: We used whole-body Kcnh6 knockout (KO) mice as model mice and fed the mice a standard chow diet (SD) and/or high-fat diet (HFD) to evaluate the responsiveness of the liver. Glucose and lipid metabolisms were detected in mice. Genes participating in cholesterol biosynthesis and fatty acid β-oxidation pathways were also evaluated using Western blot and qPCR experiments. Metabolic cage and seahorse metabolic flux were conducted to confirm mitochondrial function.
RESULTS: KCNH6 knockout impaired glucose metabolism through the AKT pathway. KCNH6 deficiency caused increased obesity and aggravated insulin resistance. KO mice exhibited aggravated HFD-induced hepatic steatosis, which was associated with dysregulation of the ACCα signaling pathway. Genetic ablation of KCNH6 resulted in altered expression profiles of genes participating in cholesterol biosynthesis and fatty acid β-oxidation pathways. KCNH6 knockout also altered cholesterol synthesis and β-oxidation of fatty acids. In addition, KCNH6 loss impaired energy metabolism and mitochondrial function. Mechanistically, KCNH6 knockout increased inflammation via NF-κB signaling pathway through interaction with IKKβ directly.
CONCLUSIONS: In conclusion, our data showed that KCNH6 exerts an important role in the regulation of hepatic lipid metabolism through mitochondrial functional pathways.