Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea.
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
Diabetes. 2016 Oct;65(10):2876-87. doi: 10.2337/db16-0223. Epub 2016 Jul 6.
Hepatic steatosis is associated with increased insulin resistance and tricarboxylic acid (TCA) cycle flux, but decreased ketogenesis and pyruvate dehydrogenase complex (PDC) flux. This study examined whether hepatic PDC activation by inhibition of pyruvate dehydrogenase kinase 2 (PDK2) ameliorates these metabolic abnormalities. Wild-type mice fed a high-fat diet exhibited hepatic steatosis, insulin resistance, and increased levels of pyruvate, TCA cycle intermediates, and malonyl-CoA but reduced ketogenesis and PDC activity due to PDK2 induction. Hepatic PDC activation by PDK2 inhibition attenuated hepatic steatosis, improved hepatic insulin sensitivity, reduced hepatic glucose production, increased capacity for β-oxidation and ketogenesis, and decreased the capacity for lipogenesis. These results were attributed to altered enzymatic capacities and a reduction in TCA anaplerosis that limited the availability of oxaloacetate for the TCA cycle, which promoted ketogenesis. The current study reports that increasing hepatic PDC activity by inhibition of PDK2 ameliorates hepatic steatosis and insulin sensitivity by regulating TCA cycle anaplerosis and ketogenesis. The findings suggest PDK2 is a potential therapeutic target for nonalcoholic fatty liver disease.
肝脂肪变性与胰岛素抵抗和三羧酸（TCA）循环通量增加有关，但酮生成和丙酮酸脱氢酶复合物（PDC）通量减少。本研究探讨了通过抑制丙酮酸脱氢酶激酶 2（PDK2）激活肝 PDC 是否可以改善这些代谢异常。高脂饮食喂养的野生型小鼠表现出肝脂肪变性、胰岛素抵抗以及丙酮酸、TCA 循环中间产物和丙二酰辅酶 A 的水平升高，但由于 PDK2 诱导，酮生成和 PDC 活性降低。PDK2 抑制导致的肝 PDC 激活可减轻肝脂肪变性，改善肝胰岛素敏感性，降低肝葡萄糖生成，增加β氧化和酮生成能力，并减少脂肪生成能力。这些结果归因于酶活性的改变以及 TCA 补料的减少，这限制了用于 TCA 循环的草酰乙酸的可用性，从而促进了酮生成。本研究报告，通过抑制 PDK2 增加肝 PDC 活性可通过调节 TCA 循环补料和酮生成来改善肝脂肪变性和胰岛素敏感性。这些发现表明 PDK2 是治疗非酒精性脂肪性肝病的潜在治疗靶点。
