Jeoung Nam Ho, Wu Pengfei, Joshi Mandar A, Jaskiewicz Jerzy, Bock Cheryl B, Depaoli-Roach Anna A, Harris Robert A
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.
Biochem J. 2006 Aug 1;397(3):417-25. doi: 10.1042/BJ20060125.
The PDC (pyruvate dehydrogenase complex) is strongly inhibited by phosphorylation during starvation to conserve substrates for gluconeogenesis. The role of PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) in regulation of PDC by this mechanism was investigated with PDHK4-/- mice (homozygous PDHK4 knockout mice). Starvation lowers blood glucose more in mice lacking PDHK4 than in wild-type mice. The activity state of PDC (percentage dephosphorylated and active) is greater in kidney, gastrocnemius muscle, diaphragm and heart but not in the liver of starved PDHK4-/- mice. Intermediates of the gluconeogenic pathway are lower in concentration in the liver of starved PDHK4-/- mice, consistent with a lower rate of gluconeogenesis due to a substrate supply limitation. The concentration of gluconeogenic substrates is lower in the blood of starved PDHK4-/- mice, consistent with reduced formation in peripheral tissues. Isolated diaphragms from starved PDHK4-/- mice accumulate less lactate and pyruvate because of a faster rate of pyruvate oxidation and a reduced rate of glycolysis. BCAAs (branched chain amino acids) are higher in the blood in starved PDHK4-/- mice, consistent with lower blood alanine levels and the importance of BCAAs as a source of amino groups for alanine formation. Non-esterified fatty acids are also elevated more in the blood of starved PDHK4-/- mice, consistent with lower rates of fatty acid oxidation due to increased rates of glucose and pyruvate oxidation due to greater PDC activity. Up-regulation of PDHK4 in tissues other than the liver is clearly important during starvation for regulation of PDC activity and glucose homoeostasis.
在饥饿期间，丙酮酸脱氢酶复合体（PDC）会因磷酸化而受到强烈抑制，以保存底物用于糖异生。利用PDHK4基因敲除小鼠（纯合子PDHK4基因敲除小鼠）研究了丙酮酸脱氢酶激酶同工酶4（PDHK4）在通过这种机制调节PDC中的作用。与野生型小鼠相比，缺乏PDHK4的小鼠饥饿时血糖降低得更多。在饥饿的PDHK4基因敲除小鼠的肾脏、腓肠肌、膈肌和心脏中，PDC的活性状态（去磷酸化且有活性的百分比）更高，但在肝脏中并非如此。饥饿的PDHK4基因敲除小鼠肝脏中糖异生途径的中间产物浓度较低，这与由于底物供应限制导致糖异生速率降低一致。饥饿的PDHK4基因敲除小鼠血液中糖异生底物的浓度较低，这与外周组织中生成减少一致。由于丙酮酸氧化速率加快和糖酵解速率降低，饥饿的PDHK4基因敲除小鼠分离出的膈肌积累的乳酸和丙酮酸较少。饥饿的PDHK4基因敲除小鼠血液中的支链氨基酸（BCAAs）含量较高，这与血液中丙氨酸水平较低以及BCAAs作为丙氨酸形成的氨基来源的重要性一致。饥饿的PDHK4基因敲除小鼠血液中未酯化脂肪酸的升高也更多，这与由于PDC活性增强导致葡萄糖和丙酮酸氧化速率增加，从而脂肪酸氧化速率降低一致。在饥饿期间，肝脏以外组织中PDHK4的上调对于调节PDC活性和葡萄糖稳态显然很重要。
