Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

Abstract

Ceramide and sphingomyelin (SM) are major components of the double membranebound sphingolipids. Ceramide is an essential bioactive lipid involved in numerous cell processes including apoptosis, necrosis, and autophagy-dependent cell death. Inversely, SM regulates opposite cellular processes such as proliferation and migration by changing receptor-mediated signal transduction in the lipid microdomain. SM is generated through a transfer of phosphocholine from phosphatidylcholine to ceramide by SM synthases (SMSs). Research during the past several decades has revealed that the ceramide/SM balance in cellular membranes regulated by SMSs is important to decide the cell fate, survival, and proliferation. In addition, recent experimental studies utilizing SMS knockout mice and murine disease models provide evidence that SMS-regulated ceramide/SM balance is involved in human diseases. Here, we review the basic structural and functional characteristics of SMSs and focus on their cellular functions through the regulation of ceramide/SM balance in membrane microdomains. In addition, we present the pathological or physiological implications of SMSs by analyzing their role in SMS-knockout mice and human disease models. This review finally presents evidence indicating that the regulation of ceramide/SM balance through SMS could be a therapeutic target for human disorders.

Sphingomyelin synthase-related protein generates diacylglycerol via the hydrolysis of glycerophospholipids in the absence of ceramide

“…The intrinsic selectivity of SMSr, which functions upstream of DGKδ, for 16:0 and/or 16:1-containing substrates would determine the limitation of DG species utilized by DGKδ. The purification of six-transmembrane proteins, SMS and SMSr, is generally difficult (18). However, in order to analyze enzymatic activities of SMSr beyond its previously reported CPES activity, purification was first needed.…”

“…Sphingomyelin synthase (SMS) is a DG-generating enzyme (17,18). There are three isoforms, SMS1, SMS2, and SMSrelated protein (SMSr) (Table 1).…”

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

“…In the cell membrane, lipid rafts or cholesterol-sphingolipids enriched domains act as platforms for cellular and/or exogenous proteins with different functions, including the shuttling of molecules on the cell surface, organization of cell signal transduction pathways, entry for pathogens and toxins, and the formation of pathological forms of proteins [ 1 ]. For example, sphingomyelinase influences cell proliferation and migration by regulating the ceramide/sphingomyelin balance in lipid rafts and thereby changing receptor-mediated signal transduction [ 2 ].…”

“…For example, growth factors receptors (GFR) through activation of PI3K/AKT or MAPK pathways lead to survival and proliferation; dead receptors (DR) such as TRAIL and Fas activate caspase 8 and the apoptotic cascade; the chemokine receptor CXCR4 activation leads to migration; the transforming growth factor-1 β receptor (TGFR) is involved in epithelial to mesenchimal transition (EMT). CD44 is localized in rafts, but its role is unclear(2). When it moves out of them, it is able to interact with the metalloproteinase 10[90] and with ezrin, leading to actin remodelling and cell migration.…”

Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

“…Phospholipid deficiencies such as the level of ethanolamine plasmalogen relative to phosphatidylethanolamine levels were observed in postmortem brain tissue of AD patients (Ginsberg et al, 1995 ). Ceramide has been of particular interest given the paradigm of the ceramide-sphingosine-1-P (S-1-P) rheostat where the balance of these two closely linked and regulated lipids may determine cell death vs. survival (reviewed in Hait et al, 2006 ; Taniguchi and Okazaki, 2020 ). While ceramide has been shown to have pro-apoptotic, autophagic, and inflammatory effects, S-1-P has a pro-survival effect mediated by G-protein coupled receptor signaling.…”