Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
Mol Cell Proteomics. 2011 Nov;10(11):M111.008094. doi: 10.1074/mcp.M111.008094. Epub 2011 Aug 9.
Lipodystrophy is a major disease involving severe alterations of adipose tissue distribution and metabolism. Mutations in genes encoding the nuclear envelope protein lamin A or its processing enzyme, the metalloproteinase Zmpste24, cause diverse human progeroid syndromes that are commonly characterized by a selective loss of adipose tissue. Similarly to humans, mice deficient in Zmpste24 accumulate prelamin A and display phenotypic features of accelerated aging, including lipodystrophy. Herein, we report the proteome and phosphoproteome of adipose tissue as well as serum metabolome in lipodystrophy by using Zmpste24(-/-) mice as experimental model. We show that Zmpste24 deficiency enhanced lipolysis, fatty acid biogenesis and β-oxidation as well as decreased fatty acid re-esterification, thus pointing to an increased partitioning of fatty acid toward β-oxidation and away from storage that likely underlies the observed size reduction of Zmpste24-null adipocytes. Besides the mitochondrial proteins related to lipid metabolism, other protein networks related to mitochondrial function, including those involved in tricarboxylic acid cycle and oxidative phosphorylation, were up-regulated in Zmpste24(-/-) mice. These results, together with the observation of an increased mitochondrial response to oxidative stress, support the relationship between defective prelamin A processing and mitochondrial dysfunction and highlight the relevance of oxidative damage in lipoatrophy and aging. We also show that absence of Zmpste24 profoundly alters the processing of the cytoskeletal protein vimentin and identify a novel protein dysregulated in lipodystrophy, High-Mobility Group Box-1 Protein. Finally, we found several lipid derivates with important roles in energy balance, such as Lysophosphatidylcholine or 2-arachidonoylglycerol, to be dysregulated in Zmpste24(-/-) serum. Together, our findings in Zmpste24(-/-) mice may be useful to unveil the mechanisms underlying adipose tissue dysfunction and its overall contribution to body homeostasis in progeria and other lipodystrophy syndromes as well as to develop novel strategies to prevent or ameliorate these diseases.
脂肪营养不良是一种涉及脂肪组织分布和代谢严重改变的主要疾病。编码核包膜蛋白 lamin A 或其加工酶金属蛋白酶 Zmpste24 的基因突变导致多种人类早衰综合征，这些综合征通常表现为脂肪组织的选择性丧失。与人类一样，缺乏 Zmpste24 的小鼠会积累前 lamin A 并表现出加速衰老的表型特征，包括脂肪营养不良。在此，我们使用 Zmpste24(-/-)小鼠作为实验模型，报道了脂肪营养不良的脂肪组织蛋白质组和磷酸化蛋白质组以及血清代谢组。我们表明，Zmpste24 缺乏增强了脂肪分解、脂肪酸生物合成和β-氧化，同时减少了脂肪酸再酯化，这表明脂肪酸向β-氧化的分配增加，而向储存的分配减少，这可能是观察到 Zmpste24 缺失脂肪细胞大小减小的原因。除了与脂质代谢相关的线粒体蛋白外，其他与线粒体功能相关的蛋白质网络，包括涉及三羧酸循环和氧化磷酸化的蛋白质网络，在 Zmpste24(-/-)小鼠中上调。这些结果，加上观察到线粒体对氧化应激的反应增强，支持了缺陷前 lamin A 加工与线粒体功能障碍之间的关系，并强调了氧化损伤在脂肪营养不良和衰老中的相关性。我们还表明，缺乏 Zmpste24 会深刻改变细胞骨架蛋白波形蛋白的加工，并鉴定出一种在脂肪营养不良中失调的新型蛋白质，即高迁移率族框 1 蛋白。最后，我们发现了几种在能量平衡中起重要作用的脂质衍生物，如溶血磷脂酰胆碱或 2-花生四烯酸甘油，在 Zmpste24(-/-)血清中失调。总之，我们在 Zmpste24(-/-)小鼠中的发现可能有助于揭示脂肪组织功能障碍的机制及其在早衰和其他脂肪营养不良综合征中对身体内稳态的整体贡献，并开发预防或改善这些疾病的新策略。
