Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding
Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding
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DOI：
10.2337/diabetes.49.5.775
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发表时间：
2000-05-01
期刊：
影响因子：
7.7
通讯作者：
Sugden, MC
中科院分区：
文献类型：
--
作者：
Holness, MJ;Kraus, A;Sugden, MC
在使用针对重组丙酮酸脱氢酶激酶 (PDK) 同工型 PDK2 和 PDK4 的抗体进行蛋白质印迹分析时，本研究证明了特定骨骼肌类型中响应高脂肪喂养的选择性 PDK 同工型断裂，这与丙酮酸对 PDK 活性调节的改变有关。高饱和脂肪饮食可使典型慢肌（比目鱼肌 [SOL]）和典型快肌（胫骨前肌 [AT]）的 PDK 活性稳定（接近 2 倍）增加。蛋白质印迹分析显示，高脂肪喂养显着增加（类似于 2 倍；P < 0.001）SOL 中的 PDK4 蛋白表达，PDK2 蛋白表达适度增加（1.3 倍）。SOL 中 PDK4 蛋白表达的相对增加与引发 50% 活性丙酮酸脱氢酶复合物所需的丙酮酸浓度增加 7.6 倍相关，这表明灵敏度显着下降PDK 受丙酮酸抑制。在 AT 肌肉中，高脂肪喂养引起 PDK4 和 PDK2 蛋白表达的相当（1.5 至 1.7 倍）增加（P < 0.05）。 PDK 对丙酮酸抑制的敏感性丧失不太明显。数据表明，PDK4 表达的增加与肌肉使用脂质衍生燃料作为呼吸底物的倾向之间存在正相关，而不是与高脂肪喂养在骨骼肌中诱导的胰岛素抵抗程度之间存在正相关。总之，高脂肪喂养导致慢肌中 PDK4 表达选择性上调，以响应体内高脂肪喂养，这与 PDK 活性对丙酮酸急性抑制的敏感性显着丧失相关。因此，PDK4 表达增加可能是在慢肌中观察到的 PDK 调节特征稳定改变的基础，以响应高脂肪喂养。
In using Western blot analysis with antibodies raised against recombinant pyruvate dehydrogenase kinase (PDK) isoforms PDK2 and PDK4, this study demonstrates selective PDK isoform snitching in specific skeletal muscle types in response to high-fat feeding that is associated with altered regulation of PDK activity by pyruvate. The administration of a diet high in saturated fats led to stable (similar to 2-fold) increases in PDK activities in both a typical slow-twitch (soleus [SOL]) muscle and a typical fast-twitch (anterior tibialis [AT]) muscle. Western blot analysis revealed that high-fat feeding significantly increased (similar to 2-fold; P < 0.001) PDK4 protein expression in SOL, with a modest (1.3-fold) increase in PDK2 protein expression, The relative increase in PDK4 protein expression in SOL was associated with a 7.6-fold increase in the pyruvate concentration that was required to elicit a 50%, active pyruvate dehydrogenase complex, which indicates a marked decrease in the sensitivity of PDK to inhibition by pyruvate. In AT muscle, high-fat feeding elicited comparable (1.5- to 1.7-fold) increases (P < 0.05) in PDK4 and PDK2 protein expression. Loss of sensitivity of PDK to inhibition by pyruvate was less marked. The data suggest that a positive correlation exists between increases in PDK4 expression and the propensity with which muscles use lipid-derived fuels as respiratory substrates rather than with the degree of insulin resistance induced in skeletal muscles by high-fat feeding. In conclusion, high-fat feeding leads to selective upregulation of PDK4 expression in slow-twitch muscle in response to high-fat feeding in vivo, which is associated with a pronounced loss of sensitivity of PDK activity to acute inhibition by pyruvate. Thus, increased PDK4 expression may underlie the stable modification of the regulatory characteristics of PDK observed in slow-twitch muscle in response to high-fat feeding.