Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Center of Clinical Research, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214023, PR China; Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, PR China.
Theranostics. 2020 May 15;10(14):6149-6166. doi: 10.7150/thno.46053. eCollection 2020.
Reduced hepatic Na/K-ATPase (NKA) activity and NKAα1 expression are engaged in the pathologies of metabolism diseases. The present study was designed to investigate the potential roles of NKAα1 in hepatic gluconeogenesis and glycogenesis in both hepatocytes and obese diabetic mice. : Insulin resistance was mimicked by glucosamine (GlcN) in either human hepatocellular carcinoma (HepG2) cells or primary mouse primary hepatocytes. Obese diabetic mice were induced by high-fat diet (HFD) feeding for 12 weeks. : We found that both NKA activity and NKAα1 protein level were downregulated in GlcN-treated hepatocytes and in the livers of obese diabetic mice. Pharmacological inhibition of NKA with ouabain worsened, while activation of NKAα1 with an antibody against an extracellular DR region of NKAα1 subunit (DR-Ab) prevented GlcN-induced increase in gluconeogenesis and decrease in glycogenesis. Likewise, the above results were also corroborated by the opposite effects of genetic knockout/overexpression of NKAα1 on both gluconeogenesis and glycogenesis. In obese diabetic mice, hepatic activation or overexpression of NKAα1 stimulated the PI3K/Akt pathway to suppress hyperglycemia and improve insulin resistance. More importantly, loss of NKA activities in NKAα1 mice was associated with more susceptibility to insulin resistance following HFD feeding. : Our findings suggest that NKAα1 is a physiological regulator of glucose homoeostasis and its DR-region is a novel target to treat hepatic insulin resistance.
NKAα1 在肝糖异生和糖生成中的作用及其与代谢疾病关系的研究
NKAα1 是一种 Na+/K+-ATP 酶（NKA）的α 亚基，其活性和表达降低与代谢疾病的病理过程有关。本研究旨在探讨 NKAα1 在肝细胞和肥胖型糖尿病小鼠肝脏中的糖异生和糖生成中的潜在作用。在人肝癌细胞（HepG2 细胞）或原代小鼠肝细胞中，用氨基葡萄糖（GlcN）模拟胰岛素抵抗。用高脂饮食（HFD）喂养肥胖型糖尿病小鼠 12 周诱导肥胖型糖尿病。我们发现，GlcN 处理的肝细胞和肥胖型糖尿病小鼠肝脏中的 NKA 活性和 NKAα1 蛋白水平均下调。用哇巴因抑制 NKA 会加重，而用针对 NKAα1 亚基细胞外 DR 区的抗体（DR-Ab）激活 NKAα1 可防止 GlcN 诱导的糖异生增加和糖生成减少。同样，NKAα1 的基因敲除/过表达对糖异生和糖生成的相反作用也证实了上述结果。在肥胖型糖尿病小鼠中，肝 NKAα1 的激活或过表达可刺激 PI3K/Akt 通路抑制高血糖和改善胰岛素抵抗。更重要的是，在 HFD 喂养后，NKAα1 小鼠中 NKA 活性的丧失与对胰岛素抵抗的易感性增加有关。我们的研究结果表明，NKAα1 是葡萄糖稳态的生理调节剂，其 DR 区是治疗肝胰岛素抵抗的新靶点。
