Impact of Peripheral Ketolytic Deficiency on Hepatic Ketogenesis and Gluconeogenesis during the Transition to Birth
Impact of Peripheral Ketolytic Deficiency on Hepatic Ketogenesis and Gluconeogenesis during the Transition to Birth
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DOI：
10.1074/jbc.m113.454868
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发表时间：
2013-07-05
影响因子：
4.8
通讯作者：
Crawford, Peter A.
中科院分区：
文献类型：
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作者：
Cotter, David G.;Ercal, Baris;Crawford, Peter A.
在从富含碳水化合物的胎儿饮食到高脂肪、低碳水化合物的新生儿饮食的转变过程中保持生物能稳态需要诱导肝脂肪酸氧化、糖异生和生酮。肝外线粒体酶 CoA 转移酶（琥珀酰辅酶 A：3-含氧酸 CoA 转移酶，SCOT，由核 Oxct1 编码）功能丧失突变的小鼠不能最终氧化酮体，并在出生后 48 小时内发生致命的高酮性低血糖。在这里，我们使用这个模型来证明，在摄入高脂肪母乳后，酮体氧化的丧失（一种完全肝外的过程）会破坏肝脏中间代谢稳态。 SCOT 敲除 (SCOT-KO) 新生儿的肝脏诱导编码过氧化物酶体增殖物激活受体 γ 共激活剂 1a (PGC-1 α)、磷酸烯醇丙酮酸羧激酶 (PEPCK)、丙酮酸羧化酶和葡萄糖 6-磷酸酶的基因表达，并且新生儿的糖异生丙氨酸和乳酸库分别减少50%。基于 NMR 的 C-13 标记底物定量命运图谱显示，SCOT-KO 新生小鼠的肝脏从外源给予的丙酮酸中合成葡萄糖。然而，外源性丙酮酸作为乙酰辅酶A对三羧酸循环的贡献在SCOT-KO肝脏中增加，并且与脂肪酸末端氧化减少相关。母乳引发高酮血症后，SCOT-KO 小鼠的肝脏从头开始合成 β-羟基丁酸，减少了 90%。破坏 β-羟基丁酸的产生会使肝脏 NAD(+)/NADH 比率增加 3 倍，氧化肝脏中的氧化还原电位，但不会氧化骨骼肌。总之，这些结果表明，外周酮体氧化可预防低血糖并支持肝脏代谢稳态，这对于适应出生期间维持血糖至关重要。
Preservation of bioenergetic homeostasis during the transition from the carbohydrate-laden fetal diet to the high fat, low carbohydrate neonatal diet requires inductions of hepatic fatty acid oxidation, gluconeogenesis, and ketogenesis. Mice with loss-of-function mutation in the extrahepatic mitochondrial enzyme CoA transferase (succinyl-CoA: 3-oxoacid CoA transferase, SCOT, encoded by nuclear Oxct1) cannot terminally oxidize ketone bodies and develop lethal hyperketonemic hypoglycemia within 48 h of birth. Here we use this model to demonstrate that loss of ketone body oxidation, an exclusively extrahepatic process, disrupts hepatic intermediary metabolic homeostasis after high fat mother's milk is ingested. Livers of SCOT-knock-out (SCOT-KO) neonates induce the expression of the genes encoding peroxisome proliferator-activated receptor gamma co-activator-1a (PGC-1 alpha), phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase, and glucose-6-phosphatase, and the neonate's pools of gluconeogenic alanine and lactate are each diminished by 50%. NMR-based quantitative fate mapping of C-13-labeled substrates revealed that livers of SCOT-KO newborn mice synthesize glucose from exogenously administered pyruvate. However, the contribution of exogenous pyruvate to the tricarboxylic acid cycle as acetyl-CoA is increased in SCOT-KO livers and is associated with diminished terminal oxidation of fatty acids. After mother's milk provokes hyperketonemia, livers of SCOT-KO mice diminish de novo hepatic beta-hydroxybutyrate synthesis by 90%. Disruption of beta-hydroxybutyrate production increases hepatic NAD(+)/NADH ratios 3-fold, oxidizing redox potential in liver but not skeletal muscle. Together, these results indicate that peripheral ketone body oxidation prevents hypoglycemia and supports hepatic metabolic homeostasis, which is critical for the maintenance of glycemia during the adaptation to birth.