Habets Daphna D J, Luiken Joost J F P, Ouwens Margriet, Coumans Will A, Vergouwe Monique, Maarbjerg Stine J, Leitges Michael, Bonen Arend, Richter Erik A, Glatz Jan F C
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University Maastricht, Netherlands.
Front Physiol. 2012 Sep 11;3:361. doi: 10.3389/fphys.2012.00361. eCollection 2012.
The signaling pathways involved in the regulation of cardiac GLUT4 translocation/glucose uptake and CD36 translocation/long-chain fatty acid uptake are not fully understood. We compared in heart/muscle-specific PKC-λ knockout mice the roles of atypical PKCs (PKC-ζ and PKC-λ) in regulating cardiac glucose and fatty acid uptake.
Neither insulin-stimulated nor AMPK-mediated glucose and fatty acid uptake were inhibited upon genetic PKC-λ ablation in cardiomyocytes. In contrast, myristoylated PKC-ζ pseudosubstrate inhibited both insulin-stimulated and AMPK-mediated glucose and fatty acid uptake by >80% in both wild-type and PKC-λ-knockout cardiomyocytes. In PKC-λ knockout cardiomyocytes, PKC-ζ is the sole remaining atypical PKC isoform, and its expression level is not different from wild-type cardiomyocytes, in which it contributes to 29% and 17% of total atypical PKC expression and phosphorylation, respectively.
Taken together, atypical PKCs are necessary for insulin-stimulated and AMPK-mediated glucose uptake into the heart, as well as for insulin-stimulated and AMPK-mediated fatty acid uptake. However, the residual PKC-ζ activity in PKC-λ-knockout cardiomyocytes is sufficient to allow optimal stimulation of glucose and fatty acid uptake, indicating that atypical PKCs are necessary but not rate-limiting in the regulation of cardiac substrate uptake and that PKC-λ and PKC-ζ have interchangeable functions in these processes.
参与调节心脏葡萄糖转运蛋白4（GLUT4）转位/葡萄糖摄取以及CD36转位/长链脂肪酸摄取的信号通路尚未完全明确。我们在心脏/肌肉特异性蛋白激酶C-λ（PKC-λ）基因敲除小鼠中比较了非典型蛋白激酶C（PKC-ζ和PKC-λ）在调节心脏葡萄糖和脂肪酸摄取中的作用。
在心肌细胞中进行PKC-λ基因敲除后，胰岛素刺激的以及腺苷酸活化蛋白激酶（AMPK）介导的葡萄糖和脂肪酸摄取均未受到抑制。相反，在野生型和PKC-λ基因敲除的心肌细胞中，肉豆蔻酰化的PKC-ζ假底物均能使胰岛素刺激的以及AMPK介导的葡萄糖和脂肪酸摄取受到超过80%的抑制。在PKC-λ基因敲除的心肌细胞中，PKC-ζ是唯一剩余的非典型PKC亚型，其表达水平与野生型心肌细胞无异，在野生型心肌细胞中，它分别占非典型PKC总表达和磷酸化的29%和17%。
综上所述，非典型蛋白激酶C对于胰岛素刺激的以及AMPK介导的心脏葡萄糖摄取，以及胰岛素刺激的和AMPK介导的脂肪酸摄取是必需的。然而，PKC-λ基因敲除的心肌细胞中残留的PKC-ζ活性足以实现对葡萄糖和脂肪酸摄取的最佳刺激，这表明非典型蛋白激酶C在心脏底物摄取调节中是必需的，但不是限速因素，并且PKC-λ和PKC-ζ在这些过程中具有可互换的功能。
