Sphingolipids and cell death

Abstract

Sphingolipids (SLs) have been considered for many years as predominant building blocks of biological membranes with key structural functions and little relevance in cellular signaling. However, this view has changed dramatically in recent years with the recognition that certain SLs such as ceramide, sphingosine 1-phosphate and gangliosides, participate actively in signal transduction pathways, regulating many different cell functions such as proliferation, differentiation, adhesion and cell death. In particular, ceramide has attracted considerable attention in cell biology and biophysics due to its key role in the modulation of membrane physical properties, signaling and cell death regulation. This latter function is largely exerted by the ability of ceramide to activate the major pathways governing cell death such as the endoplasmic reticulum and mitochondria. Overall, the evidence so far indicates a key function of SLs in disease pathogenesis and hence their regulation may be of potential therapeutic relevance in different pathologies including liver diseases, neurodegeneration and cancer biology and therapy.

Lipid signalling in disease

“…The turnover of sphingolipids can yield potent signalling molecules. Cleavage of sphingomyelin by sphingomyelinase (SMase) generates ceramide, which promotes apoptosis, cellcycle arrest and cellular senescence (see REFS 140,141 and the review by Hannun and Obeid in this issue). Ceramide can be phosphorylated by ceramide kinase (CerK) to form ceramide-1-phosphate (C1P), which has mitogenic properties, antagonizes the pro-apoptotic action of ceramide and promotes inflammation 41 .…”

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

“…Among known proapoptotic cellular messengers, the sphingolipid ceramide is a well-characterized death effector in various experimental models and pathological conditions (6)(7)(8)(9). Endogenous cellular levels of ceramide increase after stimulation with different proapoptotic factors that cause acute and chronic disease (10,11).…”

Glycolipid Content of the Nuclear Membrane in Hypoxic Rat Brain

“…Most probably the high content of gangliosides is associated with their neuroprotective effect although some gangliosides are highly expressed in pathological conditions (10). It is supposed that gangliosides may promote neuronal regeneration through modulation of trophic factors (14,18).…”