Lee Yie Hou, Tan Chin Wen, Venkatratnam Abhishek, Tan Chuen Seng, Cui Liang, Loh Seong Feei, Griffith Linda, Tannenbaum Steven R, Chan Jerry Kok Yen
BioSym (Y.H.L., C.W.T., A.V., L.G., S.R.T.) and Infectious Diseases Inter-Disciplinary Research Groups (Y.H.L., L.C., S.R.T.), Singapore-MIT Alliance for Research and Technology, Singapore 138602; Saw Swee Hock School of Public Health (C.S.T.), National University of Singapore, Singapore 117597; Department of Reproductive Medicine (S.F.L., J.K.Y.C.), KK Women's and Children's Hospital, Singapore 229899; Departments of Biological Engineering (L.G.) and Chemistry (S.R.T.) and Center for Gynepathology Research (L.G.), Massachusetts Institute of Technology, Boston, Massachusetts 02139; Department of Obstetrics and Gynecology (J.K.Y.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Cancer and Stem Cell Biology Program (J.K.Y.C.), Duke-NUS Medical School, Singapore 169857.
J Clin Endocrinol Metab. 2014 Oct;99(10):E1913-21. doi: 10.1210/jc.2014-1340. Epub 2014 Jun 24.
In endometriosis, the establishment and subsistence of ectopic lesions outside the endometrium suggest an altered cellular state for pathological hyperplasia. Sphingolipids are bioactive compounds, and their biosynthesis and metabolism modulate a range of cellular processes including proliferation, migration and apoptosis. We demonstrate that aberrations in sphingolipid metabolism occur in women with endometriosis.
Targeted mass spectrometry on >120 sphingolipids were measured in the sera (n = 62), peritoneal fluid (n = 63), and endometrial tissue (n = 14) of women with and without endometriosis. Quantitative RT-PCR and immunohistochemistry were performed on endometrial tissues determine the expression levels of sphingolipid enzymes.
Sphingolipidomics identified the in vivo accumulation of numerous sphingolipids, including the functionally antagonistic glucosylceramides and ceramides in the serum and PF of women with endometriosis. We found upregulation of specific sphingolipid enzymes, namely sphingomyelin synthase 1 (SMS1), sphingomyelinase 3 (SMPD3), and glucosylceramide synthase (GCS) in the endometrium of endometriotic women with corresponding increased GlcCer, decreased sphingomyelin levels, and decreased apoptosis in the endometrium.
Our sphingolipidomics approach provided evidence of altered sphingolipid metabolism flux in serum, peritoneal fluid, and endometrial tissue in women with endometriosis. The results provide new information on how sphingolipids and eutopic endometrium may contribute to the pathophysiology of endometriosis. The results also have implications for the use of sphingolipids as potential biomarkers.
在子宫内膜异位症中，子宫内膜外异位病灶的形成和维持提示细胞状态发生改变，出现病理性增生。鞘脂是生物活性化合物，其生物合成和代谢调节一系列细胞过程，包括增殖、迁移和凋亡。我们证明，子宫内膜异位症女性存在鞘脂代谢异常。
对患有和未患有子宫内膜异位症的女性的血清（n = 62）、腹腔液（n = 63）和子宫内膜组织（n = 14）中的120多种鞘脂进行靶向质谱分析。对子宫内膜组织进行定量逆转录聚合酶链反应和免疫组织化学检测，以确定鞘脂酶的表达水平。
鞘脂组学鉴定出多种鞘脂在体内蓄积，包括在子宫内膜异位症女性的血清和腹腔液中具有功能拮抗作用的葡糖神经酰胺和神经酰胺。我们发现，子宫内膜异位症女性的子宫内膜中特定鞘脂酶，即鞘磷脂合酶1（SMS1）、鞘磷脂酶3（SMPD3）和葡糖神经酰胺合酶（GCS）上调，相应地，子宫内膜中葡糖神经酰胺增加、鞘磷脂水平降低且细胞凋亡减少。
我们的鞘脂组学方法提供了证据，表明子宫内膜异位症女性的血清、腹腔液和子宫内膜组织中鞘脂代谢通量发生改变。这些结果为鞘脂和在位内膜如何影响子宫内膜异位症的病理生理学提供了新信息。这些结果对于将鞘脂用作潜在生物标志物也具有重要意义。
