Suppr超能文献

鞘脂代谢紊乱增强了子痫前期中神经酰胺诱导的自噬。

Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia.

作者信息

Melland-Smith Megan, Ermini Leonardo, Chauvin Sarah, Craig-Barnes Hayley, Tagliaferro Andrea, Todros Tullia, Post Martin, Caniggia Isabella

机构信息

a The Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital ; Toronto , ON Canada.

出版信息

Autophagy. 2015 Apr 3;11(4):653-69. doi: 10.1080/15548627.2015.1034414.

Abstract

Bioactive sphingolipids including ceramides are involved in a variety of pathophysiological processes by regulating cell death and survival. The objective of the current study was to examine ceramide metabolism in preeclampsia, a serious disorder of pregnancy characterized by oxidative stress, and increased trophoblast cell death and autophagy. Maternal circulating and placental ceramide levels quantified by tandem mass spectrometry were elevated in pregnancies complicated by preeclampsia. Placental ceramides were elevated due to greater de novo synthesis via high serine palmitoyltransferase activity and reduced lysosomal breakdown via diminished ASAH1 expression caused by TGFB3-induced E2F4 transcriptional repression. SMPD1 activity was reduced; hence, sphingomyelin degradation by SMPD1 did not contribute to elevated ceramide levels in preeclampsia. Oxidative stress triggered similar changes in ceramide levels and acid hydrolase expression in villous explants and trophoblast cells. MALDI-imaging mass spectrometry localized the ceramide increases to the trophophoblast layers and syncytial knots of placentae from pregnancies complicated by preeclampsia. ASAH1 inhibition or ceramide treatment induced autophagy in human trophoblast cells via a shift of the BOK-MCL1 rheostat toward prodeath BOK. Pharmacological inhibition of ASAH1 activity in pregnant mice resulted in increased placental ceramide content, abnormal placentation, reduced fetal growth, and increased autophagy via a similar shift in the BOK-MCL1 system. Our results reveal that oxidative stress-induced reduction of lysosomal hydrolase activities in combination with elevated de novo synthesis leads to ceramide overload, resulting in increased trophoblast cell autophagy, and typifies preeclampsia as a sphingolipid storage disorder.

摘要

包括神经酰胺在内的生物活性鞘脂通过调节细胞死亡和存活参与多种病理生理过程。本研究的目的是检测子痫前期(一种以氧化应激、滋养层细胞死亡增加和自噬增加为特征的严重妊娠疾病)中的神经酰胺代谢。通过串联质谱法定量的母体循环和胎盘神经酰胺水平在子痫前期合并妊娠中升高。胎盘神经酰胺升高是由于通过高丝氨酸棕榈酰转移酶活性进行的从头合成增加,以及由于TGFB3诱导的E2F4转录抑制导致ASAH1表达减少而使溶酶体分解减少。SMPD1活性降低;因此,SMPD1介导的鞘磷脂降解对子痫前期神经酰胺水平升高没有贡献。氧化应激在绒毛外植体和滋养层细胞中引发了神经酰胺水平和酸性水解酶表达的类似变化。基质辅助激光解吸电离成像质谱法将神经酰胺增加定位到子痫前期合并妊娠胎盘的滋养层和合体结节。ASAH1抑制或神经酰胺处理通过将BOK-MCL1变阻器转向促死亡的BOK,在人滋养层细胞中诱导自噬。对妊娠小鼠的ASAH1活性进行药理抑制导致胎盘神经酰胺含量增加、胎盘形成异常、胎儿生长减少,并通过BOK-MCL1系统的类似转变导致自噬增加。我们的结果表明,氧化应激诱导的溶酶体水解酶活性降低与从头合成增加相结合导致神经酰胺过载,从而导致滋养层细胞自噬增加,并将子痫前期典型地定义为一种鞘脂储存障碍。

相似文献

1
Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia.
Autophagy. 2015 Apr 3;11(4):653-69. doi: 10.1080/15548627.2015.1034414.
2
Placental autophagy regulation by the BOK-MCL1 rheostat.
Autophagy. 2013 Dec;9(12):2140-53. doi: 10.4161/auto.26452. Epub 2013 Oct 8.
3
Aberrant TGFβ Signalling Contributes to Dysregulation of Sphingolipid Metabolism in Intrauterine Growth Restriction.
J Clin Endocrinol Metab. 2015 Jul;100(7):E986-96. doi: 10.1210/jc.2015-1288. Epub 2015 May 5.
4
Sphingolipid Signature of Human Feto-Placental Vasculature in Preeclampsia.
Int J Mol Sci. 2020 Feb 4;21(3):1019. doi: 10.3390/ijms21031019.
5
Ceramide-induced BOK promotes mitochondrial fission in preeclampsia.
Cell Death Dis. 2018 Feb 20;9(3):298. doi: 10.1038/s41419-018-0360-0.
6
Platelet autophagic machinery involved in thrombosis through a novel linkage of AMPK-MTOR to sphingolipid metabolism.
Autophagy. 2021 Dec;17(12):4141-4158. doi: 10.1080/15548627.2021.1904495. Epub 2021 Apr 5.
7
Plasma cross-gestational sphingolipidomic analyses reveal potential first trimester biomarkers of preeclampsia.
PLoS One. 2017 Apr 6;12(4):e0175118. doi: 10.1371/journal.pone.0175118. eCollection 2017.
8
Palmitoyl-ceramide accumulation with necrotic cell death in A549 cells, followed by a steep increase in sphinganine content.
Biochim Open. 2015 Jun 21;1:11-27. doi: 10.1016/j.biopen.2015.06.001. eCollection 2015.
9
Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis.
Cell Physiol Biochem. 2020 Jan 31;54(1):110-125. doi: 10.33594/000000208.
10

引用本文的文献

1
Trophoblast Fusion in Hypertensive Disorders of Pregnancy and Preeclampsia.
Int J Mol Sci. 2025 Mar 21;26(7):2859. doi: 10.3390/ijms26072859.
2
Metabolic disorder of nutrients-an emerging field in the pathogenesis of preeclampsia.
Front Nutr. 2025 Mar 7;12:1560610. doi: 10.3389/fnut.2025.1560610. eCollection 2025.
4
Unraveling sphingolipid dynamics in late-onset preeclampsia: insights from lipidomic analysis.
Biochem Med (Zagreb). 2025 Feb 15;35(1):010707. doi: 10.11613/BM.2025.010708.
5
Sphingosine-1-Phosphate, a Marker of Endothelial Injury and Disease Severity in Preeclampsia.
Hypertension. 2025 May;82(5):914-925. doi: 10.1161/HYPERTENSIONAHA.124.24118. Epub 2025 Jan 22.
6
Autophagy in reproduction and pregnancy-associated diseases.
iScience. 2024 Oct 28;27(12):111268. doi: 10.1016/j.isci.2024.111268. eCollection 2024 Dec 20.
7
Pregnancy Metabolic Adaptation and Changes in Placental Metabolism in Preeclampsia.
Geburtshilfe Frauenheilkd. 2024 Sep 19;84(11):1033-1042. doi: 10.1055/a-2403-4855. eCollection 2024 Nov.
8
Tracing the Lipid Fingerprints of Preeclampsia.
Reprod Sci. 2025 Jan;32(1):52-63. doi: 10.1007/s43032-024-01731-4. Epub 2024 Oct 30.
9
Early pregnancy serum PFAS are associated with alterations in the maternal lipidome.
Environ Res. 2024 Dec 15;263(Pt 3):120183. doi: 10.1016/j.envres.2024.120183. Epub 2024 Oct 18.
10
Differences in HDL Remodeling during Healthy Pregnancy and Pregnancy with Cardiometabolic Complications.
Antioxidants (Basel). 2024 Aug 3;13(8):948. doi: 10.3390/antiox13080948.

本文引用的文献

3
Placental autophagy regulation by the BOK-MCL1 rheostat.
Autophagy. 2013 Dec;9(12):2140-53. doi: 10.4161/auto.26452. Epub 2013 Oct 8.
5
Sphingolipids: regulators of crosstalk between apoptosis and autophagy.
J Lipid Res. 2013 Jan;54(1):5-19. doi: 10.1194/jlr.R031278. Epub 2012 Nov 13.
6
Roles of ceramide and sphingolipids in pancreatic β-cell function and dysfunction.
Islets. 2012 May-Jun;4(3):177-87. doi: 10.4161/isl.20102.
7
Regulation and function of autophagy during cell survival and cell death.
Cold Spring Harb Perspect Biol. 2012 Jun 1;4(6):a008813. doi: 10.1101/cshperspect.a008813.
9
Sphingolipids in cancer.
Cancer Metastasis Rev. 2011 Dec;30(3-4):567-76. doi: 10.1007/s10555-011-9304-1.
10
Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
PLoS One. 2011;6(7):e21817. doi: 10.1371/journal.pone.0021817. Epub 2011 Jul 19.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验