Deusing Dorothé Jenni, Beyrer Melanie, Fitzenberger Elena, Wenzel Uwe
Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.
Biochem Biophys Res Commun. 2015 May 8;460(3):747-52. doi: 10.1016/j.bbrc.2015.03.101. Epub 2015 Mar 25.
Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors.
除了在将脂肪酸转运到线粒体中以提供β-氧化底物方面的功能外，肉碱还被证明会影响葡萄糖代谢，并抑制与糖尿病并发症相关的多种机制。在本研究中，我们将以高糖浓度液体培养基喂养的线虫秀丽隐杆线虫的mev-1突变体作为糖尿病模型，并测试补充肉碱对其热应激下生存的影响。100μM的肉碱完全阻止了由10mM葡萄糖导致的生存率降低。对sir-2.1进行RNA干扰，sir-2.1是介导肉碱作用的候选基因，结果显示沉默调节蛋白对生存率的挽救没有作用。在daf-12 RNA干扰下，肉碱对生存率的挽救作用被消除。对γ-丁基甜菜碱羟化酶2进行RNA干扰，该酶编码肉碱生物合成的关键酶，既没有增加葡萄糖毒性，也没有阻止肉碱对生存率的挽救，这表明补充肉碱对肉碱水平的影响是显著的。最后，证明肉碱既没有增加溶酶体的数量，也没有提高蛋白酶体的活性，排除了自噬或蛋白酶体降解等蛋白质降解途径参与肉碱的保护作用。总之，补充肉碱可防止秀丽隐杆线虫中由葡萄糖引起的生存率降低，这依赖于一种与脊椎动物过氧化物酶体增殖物激活受体具有高度同源性的核激素受体。
