Effects of genetic background on thermoregulation and fatty acid-induced uncoupling of mitochondria in UCP1-deficient mice
Effects of genetic background on thermoregulation and fatty acid-induced uncoupling of mitochondria in UCP1-deficient mice
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DOI：
10.1074/jbc.m100466200
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发表时间：
2001-04-13
影响因子：
4.8
通讯作者：
Kozak, LP
中科院分区：
文献类型：
--
作者：
Hofmann, WE;Liu, XT;Kozak, LP
游离脂肪酸和解偶联蛋白-1(UCP1)之间的相互作用导致线粒体失能，被认为是触发棕色脂肪产热的关键事件。最近，Matthias al；发现在UCP1缺陷小鼠和对照组小鼠中，分离的棕色脂肪线粒体被脂肪酸难以区分地失能，挑战了这一假设(Matthias，A.，Jacobson，A.，Cannon，B，和Nedergaard，J，(1999)J，Biol)。化学，274,28150-28160)。由于他们的结果是在未知的遗传背景下使用UCP1缺陷小鼠和对照小鼠获得的，我们想要明确地确定UCP1缺陷的表型与C57BL/6J和129/SvImJ同源背景上的目标Ucp1等位基因。UCP1缺失的同源基因小鼠具有非常明显的冷敏感表型；然而，F1杂交背景上的缺失小鼠具有抗寒能力。我们认为，杂种优势提供了一种补偿UCP1缺失的机制。与Matthias Stal的结果相反，我们发现UCP1缺乏的小鼠棕色脂肪线粒体中脂肪酸诱导的去能显著丧失，这反映在膜电位和氧气消耗上。与冷敏感不同，脂肪酸诱导的线粒体解偶联与UCP1缺陷小鼠的遗传背景无关。我们认为，细胞内游离脂肪酸以与文献中描述的模型一致的方式直接调节UCP1的解偶联活性。
An interaction between free fatty acids and UCP1 (uncoupling protein-1) leading to de-energization of mitochondria was assumed to be a key event for triggering heat production in brown fat. Recently, Matthias ef al;, finding indistinguishable de-energization of isolated brown fat mitochondria by fatty acids in UCP1-deficient mice and control mice, challenged this assumption (Matthias, A., Jacobsson, A., Cannon, B,, and Nedergaard, J, (1999) J, Biol. Chem, 274, 28150-28160). Since their results were obtained using UCP1-deficient and control mice on an undefined genetic background, we wanted to determine unambiguously the phenotype of UCP1 deficiency with the targeted Ucp1 allele on congenic C57BL/6J and 129/SvImJ backgrounds. UCP1-deficient congenic mice have a very pronounced cold-sensitive phenotype; however, deficient mice on the F1 hybrid background were resistant to cold. We propose that heterosis provides a mechanism to compensate for UCP1 deficiency. contrary to the results of Matthias st al,, we found a significant loss of fatty acid-induced de-energization, as reflected by membrane potential and oxygen consumption, in brown fat mitochondria from UCP1-deficient mice. Unlike cold sensitivity, fatty acid-induced uncoupling of mitochondria was independent of the genetic background of UCP1-deficient mice. We propose that intracellular free fatty acids directly regulate uncoupling activity of UCP1 in a manner consistent with models described in the literature.