tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1
tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1
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DOI：
10.1038/sj.cdd.4401636
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发表时间：
2005-06-01
影响因子：
12.4
通讯作者：
Peluso, G
中科院分区：
文献类型：
--
作者：
Giordano, A;Calvani, M;Peluso, G
近年来的研究表明细胞代谢与细胞凋亡有着密切的关系。我们已经评估了脂质代谢的变化与截断投标（tBid）在半胱天冬酶抑制剂和外源性细胞色素c的存在下处理的透化肝细胞。通过标记的棕榈酸酯的β-氧化通量的测量表明，tBid抑制β-氧化，从而导致棕榈酰辅酶A（CoA）的积累和乙酰肉毒碱和酰基肉毒碱的消耗，这是抑制肉毒碱棕榈酰转移酶-1（CPT-1）的特异性。我们还表明，tBid降低CPT-1活性的机制独立于丙二酰辅酶A，CPT-1的关键抑制分子，和巴克和/或Bax，但依赖于心磷脂减少。能够与CPT-1相互作用的Bcl-2的过表达抵消了tBid对β-氧化的影响。tBid在调节脂质β-氧化中的意外作用表明了一种模型，其中tBid诱导的代谢下降导致毒性脂质代谢物如棕榈酰辅酶A的积累，其可能成为凋亡途径的参与者。
Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of beta-oxidation flux by labeled palmitate demonstrates that tBid inhibits beta-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyl-transferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on beta-oxidation. The unexpected role of tBid in the regulation of lipid beta-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.