脂肪是构成生命体的重要成分,机体从外界吸收的脂肪通常以脂滴的形式储存在脂肪组织中。在病理条件下,诸如肥胖及脂质营养不良症(lipodystrophy)的病人中,非脂肪组织中也出现脂滴累积。这些异位累积的脂滴会导致器官病变,然而它们的形成机制还有待阐明。
Berardinelli-Seip先天性脂质营养不良症(BSCL2)由BSCL2/Seipin基因突变导致,是先天性脂质营养不良症中最为严重的一种。目前,人们对Seipin蛋白的分子机理仍缺乏认识。中国科学院遗传与发育生物学研究所黄勋实验室以果蝇为模式生物,建立了BSCL2病症的第一个动物模型,并以此研究脂滴异位累积的机理。研究表明:dSeipin突变果蝇的脂肪体(脂肪组织)中的脂肪储积量大大降低,并在唾液腺(非脂肪组织)中发现了脂滴累积。dSeipin突变中异常累积的脂滴表型能被仅在唾液腺特异表达的dSeipin蛋白挽救,并不依赖于其旁侧的脂肪组织,说明dSeipin蛋白在唾液腺中可以抑制脂滴的形成。
进一步的遗传互作分析表明,dSeipin可能通过影响磷脂酸(PA)的代谢从而抑制唾液腺中的脂肪形成。同时,对dSeipin突变果蝇进行脂质成分分析,发现dSeipin突变果蝇体内的磷脂酸(PA)含量升高。
这一研究初步揭示了Seipin的生理功能,并发现在脂质营养不良病症中存在着一种组织自主的机制以阻止异位脂滴累积,加深了对脂滴异位累积过程的认识。dSeipin模型是果蝇中的第一个脂滴异位累积的模型,为后续大规模挖掘控制脂滴异位累积的基因,阐明其分子机理奠定了基础。
该研究结果发表在4月14日的《公共科学图书馆—遗传学》 PLoS Genetics 杂志上,该实验室在读博士生田嫄、毕俊峰为该论文共同第一作者。该项研究获得了科技部、基金委项目的资助。(生物谷Bioon.com)
生物谷推荐原文出处:
PLoS Genet 7(4): e1001364. doi:10.1371/journal.pgen.1001364
Tissue-Autonomous Function of Drosophila Seipin in Preventing Ectopic Lipid Droplet Formation
Yuan Tian1,2#, Junfeng Bi1,2#, Guanghou Shui3, Zhonghua Liu1, Yanhui Xiang1,2, Yuan Liu1,2, Markus R. Wenk4,5, Hongyuan Yang6, Xun Huang1*
1 Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China, 2 Graduate School of Chinese Academy of Sciences, Beijing, China, 3 Life Science Institute, National University of Singapore, Singapore, Singapore, 4 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, 5 Department of Biological Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, 6 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
Abstract
Obesity is characterized by accumulation of excess body fat, while lipodystrophy is characterized by loss or absence of body fat. Despite their opposite phenotypes, these two conditions both cause ectopic lipid storage in non-adipose tissues, leading to lipotoxicity, which has health-threatening consequences. The exact mechanisms underlying ectopic lipid storage remain elusive. Here we report the analysis of a Drosophila model of the most severe form of human lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy 2, which is caused by mutations in the BSCL2/Seipin gene. In addition to reduced lipid storage in the fat body, dSeipin mutant flies accumulate ectopic lipid droplets in the salivary gland, a non-adipose tissue. This phenotype was suppressed by expressing dSeipin specifically within the salivary gland. dSeipin mutants display synergistic genetic interactions with lipogenic genes in the formation of ectopic lipid droplets. Our data suggest that dSeipin may participate in phosphatidic acid metabolism and subsequently down-regulate lipogenesis to prevent ectopic lipid droplet formation. In summary, we have demonstrated a tissue-autonomous role of dSeipin in ectopic lipid storage in lipodystrophy.