Acyl Coenzyme A Thioesterase 7 Regulates Neuronal Fatty Acid Metabolism To Prevent Neurotoxicity
Acyl Coenzyme A Thioesterase 7 Regulates Neuronal Fatty Acid Metabolism To Prevent Neurotoxicity
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DOI：
10.1128/mcb.01548-12
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发表时间：
2013-05-01
影响因子：
5.3
通讯作者：
Wolfgang, Michael J.
中科院分区：
文献类型：
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作者：
Ellis, Jessica M.;Wong, William;Wolfgang, Michael J.
许多神经系统疾病与脂质代谢失调有关;然而，神经元中脂肪酸代谢的基本代谢控制仍然是个谜。在这里，我们已经表明，神经元具有丰富的表达和活性的长链胞质酰基辅酶A（酰基辅酶A）硫酯酶7（ACOT 7），以调节脂质潴留和代谢。对在神经系统中有条件敲除ACOT 7的禁食小鼠Acot 7（N-/-）进行的无偏倚和靶向代谢组学分析显示，进入多个长链酰基辅酶A依赖性途径的脂肪酸通量增加。Acot 7（N-/-）小鼠脑脂肪酸代谢的改变伴随着瘦体重减轻、代谢亢进、肝脂肪变性、血脂异常和行为过度兴奋。这些适应性能量代谢的失败在神经退行性疾病中很常见。一致地，Acot 7（N-/-）小鼠表现出神经功能障碍和神经变性。这些数据表明，ACOT 7反调节神经元中的脂肪酸代谢，并防止神经毒性。
Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7(N-/-), revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7(N-/-) mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7(N-/-) mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity.