Abstract
Sphingolipids are a heterogeneous class of lipids and essential components of the plasma membrane and plasma lipoproteins. Studies have shown that plasma deoxysphingolipid (DSL), a newly identified sphingolipid class, is increased in diabetic patients and associated with diabetic neuropathy. However, it remains unknown if there is a causal relationship between plasma DSL increase and diabetic neuropathy. Since matrix metalloproteinases (MMPs) play an important role in diabetic neuropathy by degrading extracellular matrix in the peripheral nervous system, we investigated the effect of DSLs on the expression of MMPs and tissue inhibitor of metalloproteinase (TIMPs), and cytotoxicity in human Schwann cells. We quantified protein secretion, gene expression, and collagenase activity, and performed cytotoxicity assays. Results showed that DSLs upregulated MMP-1, downregulated TIMP-1, and induced cytotoxicity in Schwann cells. Furthermore, we quantified DSLs in VLDL, LDL, HDL2, and HDL3 isolated from type 2 diabetes mellitus (T2DM) patients with or without neuropathy. Interestingly, lipidomic analysis showed that only HDL2 isolated from T2DM patients with neuropathy contains significantly higher level of DSLs than that isolated from T2DM patients without neuropathy. Additionally, results showed that HDL2 isolated from T2DM patients with neuropathy was more potent than that isolated from T2DM patients without neuropathy in upregulating MMP-1, downregulating TIMP-1, and stimulating collagenase activity in Schwann cell. Taken together, this study demonstrated for the first time a potential causal relationship between DSLs and diabetic neuropathy and that DSL-containing HDL2 from T2DM patients with neuropathy was more potent than that from T2DM patients without neuropathy in stimulating collagenase activity.
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Abbreviations
- DSL:
-
Deoxysphingolipid
- Cer:
-
Ceramide
- SM:
-
Sphingomyelin
- MMP:
-
Matrix metalloproteinase
- TIMP:
-
Tissue inhibitor of metalloproteinase
- T2DM:
-
Type 2 diabetes mellitus
- SPT:
-
Serine palmitoyltransferase
- ECM:
-
Extracellular matrix
- GAPDH:
-
Glyceraldehyde-3-phosphate dehydrogenase
- ELISA:
-
Enzyme-linked immunosorbent assay
- PCR:
-
Real-time polymerase chain reaction
- HPLC–ESI–MS/MS:
-
High-performance liquid chromatography–tandem mass spectrometry
- SR-B1:
-
Scavenger receptor class B1
- MTT:
-
3-[4,5-Dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide
- LDH:
-
Lactate dehydrogenase
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Acknowledgements
The authors are grateful to the patients who provided plasma for lipoprotein isolation in this study.
Funding
Financial support of this work was provided by Merit Review Grant no. BX003913 from the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs (R. L. Klein, M. F. Lopes-Virella, and Y. Huang).
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The Institutional Review Board (IRB) at the Medical University of South Carolina approved the sample collection procedures. Written informed consent was obtained from all patients.
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Semler, A., Hammad, S., Lopes-Virella, M.F. et al. Deoxysphingolipids Upregulate MMP-1, Downregulate TIMP-1, and Induce Cytotoxicity in Human Schwann Cells. Neuromol Med 24, 352–362 (2022). https://doi.org/10.1007/s12017-021-08698-4
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DOI: https://doi.org/10.1007/s12017-021-08698-4