小鼠长链脂酰辅酶A脱氢酶基因的靶向破坏揭示了脂肪酸氧化的关键作用。
Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation.
作者信息
Kurtz D M, Rinaldo P, Rhead W J, Tian L, Millington D S, Vockley J, Hamm D A, Brix A E, Lindsey J R, Pinkert C A, O'Brien W E, Wood P A
机构信息
Department of Comparative Medicine, Schools of Medicine and Dentistry, University of Alabama, Birmingham, AL 35294, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15592-7. doi: 10.1073/pnas.95.26.15592.
Abstract
Abnormalities of fatty acid metabolism are recognized to play a significant role in human disease, but the mechanisms remain poorly understood. Long-chain acyl-CoA dehydrogenase (LCAD) catalyzes the initial step in mitochondrial fatty acid oxidation (FAO). We produced a mouse model of LCAD deficiency with severely impaired FAO. Matings between LCAD +/- mice yielded an abnormally low number of LCAD +/- and -/- offspring, indicating frequent gestational loss. LCAD -/- mice that reached birth appeared normal, but had severely reduced fasting tolerance with hepatic and cardiac lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic aciduria. Approximately 10% of adult LCAD -/- males developed cardiomyopathy, and sudden death was observed in 4 of 75 LCAD -/- mice. These results demonstrate the crucial roles of mitochondrial FAO and LCAD in vivo.
摘要
脂肪酸代谢异常在人类疾病中起着重要作用，但相关机制仍知之甚少。长链酰基辅酶A脱氢酶（LCAD）催化线粒体脂肪酸氧化（FAO）的第一步。我们构建了一个FAO严重受损的LCAD缺陷小鼠模型。LCAD+/-小鼠之间的交配产生的LCAD+/-和-/-后代数量异常低，表明频繁的妊娠丢失。存活至出生的LCAD-/-小鼠外观正常，但空腹耐受性严重降低，伴有肝脏和心脏脂质沉积、低血糖、血清游离脂肪酸升高以及非酮性二羧酸尿症。约10%的成年LCAD-/-雄性小鼠发生心肌病，75只LCAD-/-小鼠中有4只出现猝死。这些结果证明了线粒体FAO和LCAD在体内的关键作用。
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