Ceramide: a novel inducer for neural tube defects

Abstract

Background Circulating plasma ceramides, a class of bioactive sphingolipids, are elevated in metabolic disorders, including obesity. Infants of women with these disorders are at 2‐ to 3‐fold greater risk for developing a neural tube defect (NTD). This study aimed to test the effects of embryonic exposure to C2‐ceramides (C2) during neural tube closure. Preliminary data shows an increase in NTDs in chick embryos after C2 exposure, and addresses potential mechanisms. Results Cell and embryo models were used to examine redox shifts after ceramide exposure. While undifferentiated P19 cells were resistant to ceramide exposure, neuronally differentiated P19 cells exhibited an oxidizing shift. Consistent with these observations, GSH E h curves revealed a shift to a more oxidized state in C2 treated embryos without increasing apoptosis or changing Pax3 expression, however cell proliferation was lower. Neural tube defects were observed in 45% of chick embryos exposed to C2, compared to 12% in control embryos. Conclusions C2 exposure during critical developmental stages increased the frequency of NTDs in the avian model. Increased ROS generation in cell culture, along with the more oxidative GSH E h profiles of C2 exposed cells and embryos, support a model wherein ceramide affects neural tube closure via altered tissue redox environments.

Temporal changes in plasma membrane lipid content induce endocytosis to regulate developmental epithelial-to-mesenchymal transition

“…Interestingly, the developing embryo regulates the expression of lipid metabolic pathways with specific spatiotemporal control, and that these expression domains activate context-dependent functions. For example, in addition to a neural crest EMT phenotype, we also note neural tube closure defects in a subset of nSMase2 knockdown embryos, consistent with the finding that exogenous ceramide induces neural tube closure defects ( 14 ) and suggests that precise levels of ceramide contribute to curvature of the neural tube epithelium.…”

“…Critical roles of bioactive lipids during development have also recently emerged. For example, signaling by S1P and LPA also regulate developmental cell migration [13][14][15] , and the bioactive lipid ceramide induces neural tube closure defects when present at ectopic levels 16 . However, the functions of plasma membrane lipids during the developmental EMTs that precede migration remain less clear.…”

“…Accordingly, sphingolipid metabolism induces EMT in cancer cell lines by reducing ceramide content to suppress apoptosis and by producing the signaling lipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) which enhance proliferation and motility in metastatic cells ( 6 – 10 ). In addition to cancer, such lipids may also play a role in development—for example, signaling by S1P and LPA regulates migration of multiple embryonic cell populations ( 11 – 13 ), and ceramide induces neural tube closure defects when present at ectopic levels ( 14 ). Yet, the functions of plasma membrane lipids during developmental EMT in vivo remain less clear.…”

The Potential Role of CERS1 in Autophagy Through PI3K/AKT Signaling Pathway in Hypophysoma

“…CERs is a key enzyme in synthesizing ceramide. 12 Located on the endoplasmic reticulum membrane, CERS1 usually synthesizes C18-ceramide and C20-ceramide. It is a CERS with the highest expression, which is mainly expressed in the cerebral cortex, hippocampal neurons, and cerebellum.…”

“…9 Recent studies suggest that CERS1 overexpression can lead to growth inhibition of tumor cells. [10][11][12] Faced with severe stress or irreparable situations, ER stress and unfolded protein response (UPR) can lead to cell death and autophagy, which is an important mechanism for inhibiting tumor development. 13 In hypophysoma, the relationship between CERS1 and tumor autophagy has not been thoroughly studied yet.…”