Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects
Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects
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DOI：
10.1093/hmg/ddt382
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发表时间：
2013-12-20
影响因子：
3.5
通讯作者：
Wanders, Ronald J. A.
中科院分区：
文献类型：
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作者：
Houten, Sander M.;Herrema, Hilde;Wanders, Ronald J. A.
线粒体脂肪酸β-氧化（FAO）作为葡萄糖节约过程的重要性由FAO遗传缺陷的患者说明，这些患者可能出现危及生命的禁食诱导的低酮性低血糖。目前尚不清楚为什么这些患者外周葡萄糖需求超过肝脏再生。在这项研究中，我们系统地解决了长链酰基辅酶A酶缺陷（LCAD KO）小鼠的禁食反应。我们证明，在LCAD KO小鼠中，禁食诱导的低血糖是由外周组织中葡萄糖需求增加引起的，导致快速的肝糖原消耗。葡萄糖异生不能补偿增加的葡萄糖需求，这不是由于肝脏生糖能力不足，而是由生糖前体供应短缺引起的。这种供应短缺的原因是葡萄糖-丙氨酸循环受到抑制，支链氨基酸代谢减少，最终蛋白质动员受损。我们的结论是，在禁食期间，FAO不仅可以节省葡萄糖，而且对于氨基酸代谢也是不可或缺的，这对于维持足够的葡萄糖生产至关重要。
The importance of mitochondrial fatty acid beta-oxidation (FAO) as a glucose-sparing process is illustrated by patients with inherited defects in FAO, who may present with life-threatening fasting-induced hypoketotic hypoglycemia. It is unknown why peripheral glucose demand outpaces hepatic gluconeogenesis in these patients. In this study, we have systematically addressed the fasting response in long-chain acyl-CoA dehydrogenase-deficient (LCAD KO) mice. We demonstrate that the fasting-induced hypoglycemia in LCAD KO mice was initiated by an increased glucose requirement in peripheral tissues, leading to rapid hepatic glycogen depletion. Gluconeogenesis did not compensate for the increased glucose demand, which was not due to insufficient hepatic glucogenic capacity but rather caused by a shortage in the supply of glucogenic precursors. This shortage in supply was explained by a suppressed glucose-alanine cycle, decreased branched-chain amino acid metabolism and ultimately impaired protein mobilization. We conclude that during fasting, FAO not only serves to spare glucose but is also indispensable for amino acid metabolism, which is essential for the maintenance of adequate glucose production.