In vitro experiments and expression patterns have long suggested important roles for the genetically related cytosolic fatty acid binding proteins (FABPs) in lipid metabolism. However, evidence for such roles in vivo has become available only recently from genetic manipulation of FABP expression in mice. Here, we summarize the fuel-metabolic phenotypes of mice lacking the genes encoding heart-type FABP (H-/- mice) or liver-type FABP (L-/- mice). Cytosolic extracts from H-/- heart and skeletal muscle and from L-/- liver showed massively reduced binding of long chain fatty acids (LCFA) and, in case of L-/- liver, also of LCFA-CoA. Uptake, oxidation, and esterification LCFA, when measured in vivo and/or ex vivo, were markedly reduced in H-/- heart and muscle and in L-/- liver. The reduced LCFA oxidation in H-/- heart and L-/- liver was not due to reduced activity of PPARa, a fatty acid-sensitive transcription factor that determines the lipid-oxidative capacity in these organs. In H-/- mice, mechanisms of compensation were partially studied and included a redistribution of muscle mitochondria as well as increases of cardiac and skeletal muscle glucose uptakes and of hepatic ketogenesis. In skeletal muscle, the altered glucose uptake included decreased basal but increased insulin-dependent components. Metabolic compensation was only partial, however, since the H-/- mice showed decreased exercise tolerance. In conclusion, the recent studies established H- and L-FABP as major determinants of regional LCFA utilization; therefore the H-/- and L-/- mice are attractive models for studying principles of fuel selection and metabolic homeostasis.

译文

:体外实验和表达模式长期以来一直表明遗传相关的胞质脂肪酸结合蛋白(FABPs)在脂质代谢中的重要作用。但是,体内这种作用的证据直到最近才从小鼠中FABP表达的基因操作中获得。在这里,我们总结了缺少编码心脏型FABP(H-/-小鼠)或肝型FABP(L-/-小鼠)的基因的小鼠的燃料代谢表型。 H-/-心脏和骨骼肌以及L-/-肝脏的胞质提取物显示长链脂肪酸(LCFA)的结合大大降低,对于L-/-肝脏,LCFA-CoA的结合也大大降低。当体内和/或离体测量时,LCFA的摄取,氧化和酯化作用在H-/-心脏和肌肉以及L-/-肝中显着降低。 H-/-心脏和L-/-肝脏中LCFA氧化的减少并不是由于PPARa的活性降低,PPARa是一种脂肪酸敏感的转录因子,决定了这些器官中脂质的氧化能力。在H-/-小鼠中,对补偿机制进行了部分研究,包括肌肉线粒体的重新分布以及心肌和骨骼肌葡萄糖摄取的增加以及肝脏生酮的发生。在骨骼肌中,葡萄糖摄取的改变包括基础减少,但胰岛素依赖性成分增加。但是,由于H-/-小鼠表现出降低的运动耐力,因此代谢补偿仅是部分的。总之,最近的研究确定了H-FABP和L-FABP是区域LCFA利用的主要决定因素。因此,H-/-和L-/-小鼠是用于研究燃料选择和代谢稳态的原理的有吸引力的模型。

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