Sun Xiaocun, Zemel Michael B
University of Tennessee, Knoxville, TN 37996, USA.
J Nutr Biochem. 2003 Apr;14(4):219-26. doi: 10.1016/s0955-2863(03)00004-4.
Previous data from this laboratory demonstrate that increased intracellular Ca(2+) ([Ca(2+)]i) coordinately regulates human and murine adipocyte lipid metabolism by stimulating lipogenesis and inhibiting lipolysis. However, recent data demonstrate metabolic uncoupling increases [Ca(2+)]i but inhibits lipogenesis by suppressing fatty acid synthase (FAS) activity. Accordingly, we have evaluated the interaction between mitochondrial uncoupling, adipocyte [Ca(2+)]i, and adipocyte lipid metabolism. Pretreatment of 3T3-L1 cells with mitochondrial uncouplers (DNP or FCCP) amplified the [Ca(2+)]i response to depolarization with KCl by 2-4 fold (p <0.001), while this increase was prevented by [Ca(2+)]i channel antagonism with lanthanum. Mitochondrial uncouplers caused rapid (within 4hr) dose-dependent inhibition of FAS activity (p <0.001), while lanthanum caused a further additive inhibition. The suppression of FAS activity induced by uncoupling was reversed by addition of ATP. Mitochondrial uncouplers increased FAS expression significantly while [Ca(2+)]i antagonism with lanthanum decreased FAS expression (P <0.001). In contrast, mitochondrial uncouplers independently inhibited basal and isoproterenol-stimulated lipolysis (20-40%, p <0.001), while this inhibition was fully reversed by lanthanum. Thus, mitochondrial uncoupling exerted short-term regulatory effects on adipocyte [Ca(2+)]i and lipogenic and lipolytic systems, serving to suppress lipolysis via a Ca(2+) -dependent mechanism and FAS activity via a Ca(2+)-independent mechanism.
该实验室之前的数据表明，细胞内钙离子浓度升高（[Ca(2+)]i）通过刺激脂肪生成和抑制脂肪分解来协同调节人和小鼠脂肪细胞的脂质代谢。然而，最近的数据表明，代谢解偶联会增加[Ca(2+)]i，但通过抑制脂肪酸合酶（FAS）活性来抑制脂肪生成。因此，我们评估了线粒体解偶联、脂肪细胞[Ca(2+)]i和脂肪细胞脂质代谢之间的相互作用。用线粒体解偶联剂（DNP或FCCP）预处理3T3-L1细胞，可使[Ca(2+)]i对氯化钾去极化的反应增强2至4倍（p <0.001），而用镧进行[Ca(2+)]i通道拮抗可阻止这种增加。线粒体解偶联剂导致FAS活性迅速（4小时内）出现剂量依赖性抑制（p <0.001），而镧则产生进一步的累加抑制作用。添加ATP可逆转解偶联诱导的FAS活性抑制。线粒体解偶联剂显著增加FAS表达，而用镧进行[Ca(2+)]i拮抗则降低FAS表达（P <0.001）。相反，线粒体解偶联剂独立抑制基础和异丙肾上腺素刺激的脂肪分解（20 - 40%，p <0.001），而这种抑制作用可被镧完全逆转。因此，线粒体解偶联对脂肪细胞[Ca(2+)]i以及脂肪生成和脂肪分解系统发挥短期调节作用，通过钙依赖机制抑制脂肪分解，并通过钙非依赖机制抑制FAS活性。
