Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db/db mice.
Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db/db mice.
复制标题
肝脏中的 Pck1 基因沉默可改善 db/db 小鼠的血糖控制、胰岛素敏感性和血脂异常。
DOI：
10.2337/db07-1087
复制
发表时间：
2008-08
期刊：
影响因子：
7.7
通讯作者：
Perales JC
中科院分区：
文献类型：
--
作者：
Gómez-Valadés AG;Méndez-Lucas A;Vidal-Alabró A;Blasco FX;Chillon M;Bartrons R;Bermúdez J;Perales JC
细胞溶质磷酸烯醇式丙酮酸羧激酶（PEPCK-C;由Pck 1编码）催化胚胎发生的第一个关键步骤。大量证据表明，PEPCK-C活性与血糖控制之间存在直接相关性。因此，我们的目的是评估代谢影响及其在2型糖尿病模型中敲低肝脏PEPCK-C的潜在机制。研究设计和方法-PEPCK-C基因的靶向是用腺病毒转导的RNAi实现的。该研究评估了糖尿病的几种临床症状和外周组织中的胰岛素信号传导，以及肝脏中基因表达、蛋白质和代谢物的变化。还评价了肝脏生物能量学。SDS处理导致PEPCK-C mRNA和蛋白质减少。治疗后，测量到改善的甘油三酯和胰岛素血症，降低的甘油三酯，以及较高的总胆固醇和HDL胆固醇。在不存在从头脂肪生成的情况下，在肝脏中观察到未灭菌脂肪酸蓄积。尽管有肝硬化，但治疗导致肝脏、肌肉和脂肪组织中胰岛素信号传导改善。在离体肝细胞中的氧消耗测量结果表明线粒体功能未改变，因此细胞能荷增加。治疗后，与肝细胞生成有关的关键调节因子（FOXO 1、肝细胞核因子-4 α和过氧化物酶体增殖物激活受体-γ共激活因子[PGC]-1α）和酶（G6 β）下调。最后，Sirt 1（一种通过PGC-1α调节胚胎发生的氧化还原状态传感器）的水平降低。结论-我们的观察表明，沉默PEPCK-C对血糖控制和能量代谢有直接影响，并为该酶作为糖尿病治疗靶点的潜在意义提供了新的见解。
OBJECTIVE—Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by Pck1) catalyzes the first committed step in gluconeogenesis. Extensive evidence demonstrates a direct correlation between PEPCK-C activity and glycemia control. Therefore, we aimed to evaluate the metabolic impact and their underlying mechanisms of knocking down hepatic PEPCK-C in a type 2 diabetic model. RESEARCH DESIGN AND METHODS—PEPCK-C gene targeting was achieved using adenovirus-transduced RNAi. The study assessed several clinical symptoms of diabetes and insulin signaling in peripheral tissues, in addition to changes in gene expression, protein, and metabolites in the liver. Liver bioenergetics was also evaluated. RESULTS—Treatment resulted in reduced PEPCK-C mRNA and protein. After treatment, improved glycemia and insulinemia, lower triglyceride, and higher total and HDL cholesterol were measured. Unsterified fatty acid accumulation was observed in the liver, in the absence of de novo lipogenesis. Despite hepatic lipidosis, treatment resulted in improved insulin signaling in the liver, muscle, and adipose tissue. O2 consumption measurements in isolated hepatocytes demonstrated unaltered mitochondrial function and a consequent increased cellular energy charge. Key regulatory factors (FOXO1, hepatocyte nuclear factor-4α, and peroxisome proliferator–activated receptor-γ coactivator [PGC]-1α) and enzymes (G6Pase) implicated in gluconeogenesis were downregulated after treatment. Finally, the levels of Sirt1, a redox-state sensor that modulates gluconeogenesis through PGC-1α, were diminished. CONCLUSIONS—Our observations indicate that silencing PEPCK-C has direct impact on glycemia control and energy metabolism and provides new insights into the potential significance of the enzyme as a therapeutic target for the treatment of diabetes.
登录
查看更多内容
影响因子：
14.9
作者：
De Souza AT;Dai X;Spencer AG;Reppen T;Menzie A;Roesch PL;He Y;Caguyong MJ;Bloomer S;Herweijer H;Wolff JA;Hagstrom JE;Lewis DL;Linsley PS;Ulrich RG
通讯作者：
Ulrich RG
影响因子：
64.8
作者：
Mitro, Nico;Mak, Puiying A.;Saez, Enrique
通讯作者：
Saez, Enrique
影响因子：
4.1
作者：
Drynan, L;Quant, PA;Zammit, VA
通讯作者：
Zammit, VA
影响因子：
7.7
作者：
Hong, Z;Yakar, S;LeRoith, D
通讯作者：
LeRoith, D
影响因子：
2.9
作者：
Kuznetsov, AV;Strobl, D;Gnaiger, E
通讯作者：
Gnaiger, E