Spiekerkoetter U, Tokunaga C, Wendel U, Mayatepek E, Exil V, Duran M, Wijburg F A, Wanders R J A, Strauss A W
University Children's Hospital, Düsseldorf, Germany.
Eur J Clin Invest. 2004 Mar;34(3):191-6. doi: 10.1111/j.1365-2362.2004.01308.x.
In humans with deficiency of the very long-chain acyl-CoA dehydrogenase (VLCAD), C14-C18 acylcarnitines accumulate. In this paper we have used the VLCAD knockout mouse as a model to study changes in blood carnitine and acylcarnitine profiles under stress.
VLCAD knockout mice exhibit stress-induced hypoglycaemia and skeletal myopathy; symptoms resembling human VLCADD. To study the extent of biochemical derangement in response to different stressors, we determined blood carnitine and acylcarnitine profiles after exercise on a treadmill, fasting, or exposure to cold.
Even in a nonstressed, well-fed state, knockout mice presented twofold higher C14-C18 acylcarnitines and a lower free carnitine of 72% as compared to wild-type littermates. After 1 h of intense exercise, the C14-C18 acylcarnitines in blood significantly increased, but free carnitine remained unchanged. After 8 h of fasting at 4 degrees C, the long-chain acylcarnitines were elevated 5-fold in knockout mice in comparison with concentrations in unstressed wild-type mice (P < 0.05), and four out of 12 knockout mice died. Free carnitine decreased to 44% as compared with unstressed wild-type mice. An increase in C14-C18 acylcarnitines and a decrease of free carnitine were also observed in fasted heterozygous and wild-type mice.
Long-chain acylcarnitines in blood increase in knockout mice in response to different stressors and concentrations correlate with the clinical condition. A decrease in blood free carnitine in response to severe stress is observed in knockout mice but also in wild-type littermates. Monitoring blood acylcarnitine profiles in response to different stressors may allow systematic analysis of therapeutic interventions in VLCAD knockout mice.
在极长链酰基辅酶A脱氢酶（VLCAD）缺乏的人类中，C14 - C18酰基肉碱会蓄积。在本文中，我们使用VLCAD基因敲除小鼠作为模型，来研究应激状态下血液中肉碱和酰基肉碱谱的变化。
VLCAD基因敲除小鼠表现出应激诱导的低血糖和骨骼肌病；症状类似于人类的VLCADD。为了研究对不同应激源反应时生化紊乱的程度，我们在小鼠进行跑步机运动、禁食或暴露于寒冷环境后，测定了血液中肉碱和酰基肉碱谱。
即使在无应激、喂养良好的状态下，与野生型同窝小鼠相比，基因敲除小鼠的C14 - C18酰基肉碱高出两倍，游离肉碱降低了72%。剧烈运动1小时后，血液中的C14 - C18酰基肉碱显著增加，但游离肉碱保持不变。在4℃禁食8小时后，与无应激的野生型小鼠相比，基因敲除小鼠的长链酰基肉碱升高了5倍（P < 0.05），12只基因敲除小鼠中有4只死亡。与无应激的野生型小鼠相比，游离肉碱降至44%。在禁食的杂合子和野生型小鼠中也观察到C14 - C18酰基肉碱增加和游离肉碱减少。
基因敲除小鼠血液中的长链酰基肉碱会因不同应激源而增加，且浓度与临床状况相关。在基因敲除小鼠以及野生型同窝小鼠中，均观察到严重应激下血液游离肉碱减少。监测对不同应激源反应时的血液酰基肉碱谱，可能有助于对VLCAD基因敲除小鼠的治疗干预进行系统分析。
