A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

Abstract

Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer’s and Parkinson’s disease, and lysosomal storage disorders.

Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

“…1a) . Because sphingosines are generated by degradation of more complex sphingolipids 13 , their reduced levels suggest that degradation of sphingolipids is impaired in PGRN-deficient brains. Unlike sphingolipids, levels of the phospholipids phosphatidylethanolamine (PE), phosphatidylcholine (PC), PS, and of neutral lipids were similar among genotypes ( Extended Data Fig.…”

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

“…The closest association of sphingolipids with neurodegenerative diseases was related to their structural function, especially the glycosphingolipids, as the main component of the plasma membrane of oligodendrocytes and myelin [9]. However, several studies have demonstrated the implication of sphingolipids in several key biological processes such as cellular proliferation and migration, differentiation, autophagy, apoptosis, senescence, and inflammation [8,[10][11][12][13][14]. Recent works on transcriptomics and electrospray ionization mass spectrometry analysis (sphingolipidomics) have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases [15][16][17].…”

Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets

“…As mentioned, ceramide species can induce endothelial dysfunction and increase vascular permeability by promoting oxidative stress, inflammation and by reducing the production of nitric oxide (NO) [40]. Therefore, ceramides are important regulators of tissue metabolism and play vital roles in pathophysiological processes with implications in cardiometabolic disease such as ATS [41], inflammation, obesity, NAFLD [42], pancreatic ß-cell dysfunction, T2DM [43], and cancer [44].…”

“…Regarding their involvement in atherogenesis, they participate by two mechanisms: one directly on the vascular wall through transcytosis of ox-LDL, and second through insulin sensitivity and dyslipidemia [44]. In different circumstances, data shows that ox-LDL is present in the atherosclerotic plaque, and that increased blood concentration especially in patients with NAFLD, mediates activation of LacCer synthase and thus, the development of ATS [45,46].…”