Critical Role for Very-Long Chain Sphingolipids in Invariant Natural Killer T Cell Development and Homeostasis

Saroha, Ashish; Pewzner-Jung, Yael; Ferreira, Natália Santos; Sharma, Piyush; Jouan, Youenn; Kelly, Samuel; Feldmesser, Ester; Merrill, Alfred H.; Trottein, François; Paget, Christophe; Lang, Karl S.; Futerman, Anthony H.

doi:10.3389/fimmu.2017.01386

Cited by 18 publications

(16 citation statements)

References 71 publications

(85 reference statements)

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“…2). In addition, the lack of iNKT cells in CerS2-null mice 37 could also affect NAFLD progression 38 . Thus, CerS2 heterozygotes were used to induce NAFLD to exclude other factors that are altered in CerS2 null mice.…”

Section: Resultsmentioning

confidence: 99%

Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases

et al. 2019

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The endoplasmic reticulum (ER) is not only important for protein synthesis and folding but is also crucial for lipid synthesis and metabolism. In the current study, we demonstrate an important role of ceramide synthases (CerS) in ER stress and NAFLD progression. Ceramide is important in sphingolipid metabolism, and its acyl chain length is determined by a family of six CerS in mammals. CerS2 generates C22-C24 ceramides, and CerS5 or CerS6 produces C16 ceramide. To gain insight into the role of CerS in NAFLD, we used a high-fat diet (HFD)-induced NAFLD mouse model. Decreased levels of CerS2 and increased levels of CerS6 were observed in the steatotic livers of mice fed a HFD. In vitro experiments with Hep3B cells indicated the protective role of CerS2 and the detrimental role of CerS6 in the ER stress response induced by palmitate treatment. In particular, CerS6 overexpression increased sterol regulatory elementbinding protein-1 (SREBP-1) cleavage with decreased levels of INSIG-1, leading to increased lipogenesis. Blocking ER stress abrogated the detrimental effects of CerS6 on palmitate-induced SREBP-1 cleavage. In accordance with the protective role of CerS2 in the palmitate-induced ER stress response, CerS2 knockdown enhanced ER stress and SREBP-1 cleavage, and CerS2 heterozygote livers exhibited a stronger ER stress response and higher triglyceride levels following HFD. Finally, treatment with a low dose of bortezomib increased hepatic CerS2 expression and protected the development of NAFLD following HFD. These results indicate that CerS and its derivatives impact hepatic ER stress and lipogenesis differently and might be therapeutic targets for NAFLD.

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Section: Resultsmentioning

confidence: 99%

Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases

et al. 2019

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“…Studies on phagocytes 28 revealed that VLC Cer could be essential for phagosome maturation in immune cells. VLC sphingolipids were found to be crucial in the survival of invariant natural killer T cells in thymus and liver 29 . At the biophysical level there are interesting studies on the properties of VLC sphingolipids dispersed in pure form in aqueous media [30][31][32][33][34][35] , but not many reports on their biophysical effects in multicomponent membranes 30,36,37 .…”

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confidence: 99%

C24:0 and C24:1 sphingolipids in cholesterol-containing, five- and six-component lipid membranes

González-Ramírez

García-Arribas

Sot

et al. 2020

Sci Rep

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The biophysical properties of sphingolipids containing lignoceric (C24:0) or nervonic (C24:1) fatty acyl residues have been studied in multicomponent lipid bilayers containing cholesterol (Chol), by means of confocal microscopy, differential scanning calorimetry and atomic force microscopy. Lipid membranes composed of dioleoyl phosphatidylcholine and cholesterol were prepared, with the addition of different combinations of ceramides (C24:0 and/or C24:1) and sphingomyelins (C24:0 and/or C24:1). Results point to C24:0 sphingolipids, namely lignoceroyl sphingomyelin (lSM) and lignoceroyl ceramide (lCer), having higher membrane rigidifying properties than their C24:1 homologues (nervonoyl SM, nSM, or nervonoyl Cer, nCer), although with a similar strong capacity to induce segregated gel phases. In the case of the lSM-lCer multicomponent system, the segregated phases have a peculiar fibrillar or fern-like morphology. Moreover, the combination of C24:0 and C24:1 sphingolipids generates interesting events, such as a generalized bilayer dynamism/instability of supported planar bilayers. In some cases, these sphingolipids give rise to exothermic curves in thermograms. These peculiar features were not present in previous studies of C24:1 combined with C16:0 sphingolipids. Conclusions of our study point to nSM as a key factor governing the relative distribution of ceramides when both lCer and nCer are present. The data indicate that lCer could be easier to accommodate in multicomponent bilayers than its C16:0 counterpart. These results are relevant for events of membrane platform formation, in the context of sphingolipid-based signaling cascades. Sphingolipids are important structural membrane lipids, as well as second messengers in diverse cellular signaling cascades 1-4. Among the sphingolipid subfamilies, ceramides (Cer) have received the attention of investigators due to their particular biophysical properties and their role in apoptotic processes 5-8. Cer are also important in the stratum corneum of the skin 9. The biophysical properties of Cer cause dramatic changes in membranes, as this sphingolipid tends to induce the formation of segregated areas ('domains'), giving rise to bilayer lateral heterogeneity 10-13. In turn the presence of domains has an impact on the diffusivity of proteins and their capacity to cluster and exert their physiological effects 14-16. Mammals have 6 ceramide synthases, of which CerS5 predominantly produces C16:0 Cer, while CerS2 yields ceramides incorporating C22-C24 fatty acids 17. For long and very-long chain Cer (longer than 14 carbons in their N-acyl group), the effects on membranes may also include lipid trans-bilayer motion, or flip-flop 18 (therefore affecting bilayer asymmetry) and a notable increase in solute permeability across the membrane 19,20 , which may decisively distort cell homeostasis. Most of the experiments classically performed with model membranes have been focused on C16:0 ceramide (pCer), as it is a simple, saturated long-chain ceramide and, more importantly, C16:0 s...

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“…; Saroha et al . ). While sulfatides with longer fatty acids are important for the stability and maintenance of the myelin sheath (Schmitt et al .…”

Section: Discussionmentioning

confidence: 97%

Sulfatide isoform pattern in cerebrospinal fluid discriminates progressive MS from relapsing‐remitting MS

Novakova

Singh

Axelsson

et al. 2018

Journal of Neurochemistry

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Several biomarkers including proteins and lipids have been reported in MS cerebrospinal fluid (CSF), reflecting different aspects of the pathophysiology particularly of relapsing-remitting MS (RRMS). Sulfatide, abundant in the myelin sheath and a proposed target for autoimmune attack in MS, has been reported altered in MS CSF. Here, we investigated the potential of CSF sulfatide and its isoforms as biomarkers in MS. A highly sensitive and quantitative mass spectrometry method was employed to determine levels of sulfatide isoforms in CSF from RRMS and progressive MS (PMS) patients, and healthy donors (HD). We demonstrate that levels of total CSF sulfatide and C24:1, C26:1, and C26:1-OH isoforms were significantly increased in PMS compared with RRMS patients and HD, while C23:0-OH was significantly decreased in CSF from PMS patients compared to the other two groups. Multivariate discriminant analysis showed that CSF sulfatide isoform pattern in PMS patients was distinct and non-overlapping with that of RRMS patients and HD. Sulfatide levels did not correlate with tested biomarkers or clinical parameters. The results suggest that CSF sulfatide isoform levels may be used to discriminate the phenotype of MS and might play a role in the progression of the disease.

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Critical Role for Very-Long Chain Sphingolipids in Invariant Natural Killer T Cell Development and Homeostasis

Cited by 18 publications

References 71 publications

Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases

Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases

C24:0 and C24:1 sphingolipids in cholesterol-containing, five- and six-component lipid membranes

Sulfatide isoform pattern in cerebrospinal fluid discriminates progressive MS from relapsing‐remitting MS

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