脂肪是構(gòu)成生命體的重要成分,，機(jī)體從外界吸收的脂肪通常以脂滴的形式儲(chǔ)存在脂肪組織中。在病理?xiàng)l件下,，諸如肥胖及脂質(zhì)營(yíng)養(yǎng)不良癥(lipodystrophy)的病人中,，非脂肪組織中也出現(xiàn)脂滴累積。這些異位累積的脂滴會(huì)導(dǎo)致器官病變,，然而它們的形成機(jī)制還有待闡明,。
Berardinelli-Seip先天性脂質(zhì)營(yíng)養(yǎng)不良癥（BSCL2）由BSCL2/Seipin基因突變導(dǎo)致，是先天性脂質(zhì)營(yíng)養(yǎng)不良癥中最為嚴(yán)重的一種,。目前,，人們對(duì)Seipin蛋白的分子機(jī)理仍缺乏認(rèn)識(shí)。中國(guó)科學(xué)院遺傳與發(fā)育生物學(xué)研究所黃勛實(shí)驗(yàn)室以果蠅為模式生物,，建立了BSCL2病癥的第一個(gè)動(dòng)物模型，并以此研究脂滴異位累積的機(jī)理,。研究表明：dSeipin突變果蠅的脂肪體（脂肪組織）中的脂肪儲(chǔ)積量大大降低,，并在唾液腺（非脂肪組織）中發(fā)現(xiàn)了脂滴累積。dSeipin突變中異常累積的脂滴表型能被僅在唾液腺特異表達(dá)的dSeipin蛋白挽救,，并不依賴于其旁側(cè)的脂肪組織,，說明dSeipin蛋白在唾液腺中可以抑制脂滴的形成。
進(jìn)一步的遺傳互作分析表明,，dSeipin可能通過影響磷脂酸(PA)的代謝從而抑制唾液腺中的脂肪形成,。同時(shí)，對(duì)dSeipin突變果蠅進(jìn)行脂質(zhì)成分分析,，發(fā)現(xiàn)dSeipin突變果蠅體內(nèi)的磷脂酸(PA)含量升高,。
這一研究初步揭示了Seipin的生理功能，并發(fā)現(xiàn)在脂質(zhì)營(yíng)養(yǎng)不良病癥中存在著一種組織自主的機(jī)制以阻止異位脂滴累積,，加深了對(duì)脂滴異位累積過程的認(rèn)識(shí),。dSeipin模型是果蠅中的第一個(gè)脂滴異位累積的模型，為后續(xù)大規(guī)模挖掘控制脂滴異位累積的基因,，闡明其分子機(jī)理奠定了基礎(chǔ),。
該研究結(jié)果發(fā)表在4月14日的《公共科學(xué)圖書館—遺傳學(xué)》 PLoS Genetics 雜志上，該實(shí)驗(yàn)室在讀博士生田嫄,、畢俊峰為該論文共同第一作者,。該項(xiàng)研究獲得了科技部、基金委項(xiàng)目的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
