PMID- 34853975 OWN - NLM STAT- MEDLINE DCOM- 20220826 LR - 20220912 IS - 1559-1174 (Electronic) IS - 1535-1084 (Linking) VI - 24 IP - 3 DP - 2022 Sep TI - Deoxysphingolipids Upregulate MMP-1, Downregulate TIMP-1, and Induce Cytotoxicity in Human Schwann Cells. PG - 352-362 LID - 10.1007/s12017-021-08698-4 [doi] AB - 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. CI - (c) 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. FAU - Semler, Andrea AU - Semler A AD - Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Hammad, Samar AU - Hammad S AD - Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, USA. FAU - Lopes-Virella, Maria F AU - Lopes-Virella MF AD - Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, USA. AD - Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Klein, Richard L AU - Klein RL AD - Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, USA. AD - Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Huang, Yan AU - Huang Y AUID- ORCID: 0000-0003-2789-5580 AD - Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, USA. huangyan@musc.edu. AD - Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA. huangyan@musc.edu. LA - eng PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20211201 PL - United States TA - Neuromolecular Med JT - Neuromolecular medicine JID - 101135365 RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - EC 3.4.24.- (Matrix Metalloproteinases) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.7 (Matrix Metalloproteinase 1) SB - IM MH - *Diabetes Mellitus, Type 2/complications MH - *Diabetic Neuropathies MH - Humans MH - Matrix Metalloproteinase 1/genetics MH - Matrix Metalloproteinase 2/genetics/metabolism MH - Matrix Metalloproteinases MH - Schwann Cells/metabolism MH - Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism OTO - NOTNLM OT - Deoxysphingolipid OT - Diabetes OT - Matrix metalloproteinase OT - Neuropathy OT - Sphingolipid EDAT- 2021/12/03 06:00 MHDA- 2022/08/27 06:00 CRDT- 2021/12/02 06:44 PHST- 2021/07/08 00:00 [received] PHST- 2021/11/18 00:00 [accepted] PHST- 2021/12/03 06:00 [pubmed] PHST- 2022/08/27 06:00 [medline] PHST- 2021/12/02 06:44 [entrez] AID - 10.1007/s12017-021-08698-4 [pii] AID - 10.1007/s12017-021-08698-4 [doi] PST - ppublish SO - Neuromolecular Med. 2022 Sep;24(3):352-362. doi: 10.1007/s12017-021-08698-4. Epub 2021 Dec 1.