Nedergaard J, Golozoubova V, Matthias A, Asadi A, Jacobsson A, Cannon B
The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden.
Biochim Biophys Acta. 2001 Mar 1;1504(1):82-106. doi: 10.1016/s0005-2728(00)00247-4.
The uniqueness of UCP1 (as compared to UCP2/UCP3) is evident from expression analysis and ablation studies. UCP1 expression is positively correlated with metabolic inefficiency, being increased by cold acclimation (in adults or perinatally) and overfeeding, and reduced in fasting and genetic obesity. Such a simple relationship is not observable for UCP2/UCP3. Studies with UCP1-ablated animals substantiate the unique role of UCP1: the phenomenon of adaptive adrenergic non-shivering thermogenesis in the intact animal is fully dependent on the presence of UCP1, and so is any kind of cold acclimation-recruited non-shivering thermogenesis; thus UCP2/UCP3 (or any other proteins or metabolic processes) cannot substitute for UCP1 physiologically, irrespective of their demonstrated ability to show uncoupling in reconstituted systems or when ectopically expressed. Norepinephrine-induced thermogenesis in brown-fat cells is absolutely dependent on UCP1, as is the uncoupled state and the recoupling by purine nucleotides in isolated brown-fat mitochondria. Although very high UCP2/UCP3 mRNA levels are observed in brown adipose tissue of UCP1-ablated mice, there is no indication that the isolated brown-fat mitochondria are uncoupled; thus, high expression of UCP2/UCP3 does not necessarily confer to the mitochondria of a tissue a propensity for being innately uncoupled. Whereas the thermogenic effect of fatty acids in brown-fat cells is fully UCP1-dependent, this is not the case in brown-fat mitochondria; this adds complexity to the issues concerning the mechanisms of UCP1 function and the pathway from beta(3)-adrenoceptor stimulation to UCP1 activation and thermogenesis. In addition to amino acid sequences conserved in all UCPs as part of the tripartite structure, all UCPs contain certain residues associated with nucleotide binding. However, conserved amongst all UCP1s so far sequenced, and without parallel in all UCP2/UCP3, are two sequences: 144SHLHGIKP and the C-terminal sequence RQTVDC(A/T)T; these sequences may therefore be essential for the unique thermogenic function of UCP1. The level of UCP1 in the organism is basically regulated at the transcriptional level (physiologically probably mainly through the beta(3)-adrenoceptor/CREB pathway), with influences from UCP1 mRNA stability and from the delay caused by translation. It is concluded that UCP1 is unique amongst the uncoupling proteins and is the only protein able to mediate adaptive non-shivering thermogenesis and the ensuing metabolic inefficiency.
从表达分析和基因敲除研究中可以明显看出UCP1（与UCP2/UCP3相比）的独特性。UCP1的表达与代谢低效呈正相关，在冷适应（成年期或围产期）和过度喂养时增加，而在禁食和遗传性肥胖时降低。UCP2/UCP3则不存在这种简单的关系。对UCP1基因敲除动物的研究证实了UCP1的独特作用：完整动物中适应性肾上腺素能非颤抖性产热现象完全依赖于UCP1的存在，任何类型的冷适应诱导的非颤抖性产热也是如此；因此，无论UCP2/UCP3（或任何其他蛋白质或代谢过程）在重组系统中或异位表达时表现出解偶联的能力如何，它们在生理上都不能替代UCP1。棕色脂肪细胞中去甲肾上腺素诱导的产热绝对依赖于UCP1，孤立的棕色脂肪线粒体中的解偶联状态和嘌呤核苷酸的再偶联也是如此。尽管在UCP1基因敲除小鼠的棕色脂肪组织中观察到非常高的UCP2/UCP3 mRNA水平，但没有迹象表明孤立的棕色脂肪线粒体是解偶联的；因此，UCP2/UCP3的高表达并不一定使组织中的线粒体具有天生解偶联的倾向。虽然棕色脂肪细胞中脂肪酸的产热效应完全依赖于UCP1，但在棕色脂肪线粒体中并非如此；这增加了关于UCP1功能机制以及从β(3)-肾上腺素能受体刺激到UCP1激活和产热途径问题的复杂性。除了作为三方结构一部分在所有UCP中保守的氨基酸序列外，所有UCP都含有与核苷酸结合相关的某些残基。然而，在迄今为止测序的所有UCP1中保守且在所有UCP2/UCP3中无类似序列的是两个序列：144SHLHGIKP和C末端序列RQTVDC(A/T)T；因此这些序列可能对UCP1独特的产热功能至关重要。生物体中UCP1的水平基本上在转录水平受到调节（生理上可能主要通过β(3)-肾上腺素能受体/CREB途径），同时受到UCP1 mRNA稳定性和翻译延迟的影响。得出的结论是，UCP1在解偶联蛋白中是独特的，并且是唯一能够介导适应性非颤抖性产热以及随之而来的代谢低效的蛋白质。
