Review Sphingolipids and their metabolism in physiology and disease, 2017, Hannun, Yusuf A. and Obeid, Lina M.

[SNT Gatchaman]

Sphingolipids and their metabolism in physiology and disease
Hannun, Yusuf A.; Obeid, Lina M.

Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome.

These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid–protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches.

Link | PDF (Nature Reviews Molecular Cell Biology)

 

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The concept of bioactive lipids and its utility for understanding cell and organismal biology has evolved over the past several decades [...] bioactive lipids are components of cellular regulatory circuits (such as signalling networks), which distinguishes them from other lipids that have structural and/or energetic functions.

We now understand that lipid metabolism is highly regulated and complex whereby many stimuli and agents affect one or more enzymes.

the universe of lipids, and especially sphingolipids, has been rather impenetrable owing to complexities in working with lipids at nearly all levels. Fortunately, important technological advances have enabled more researchers to study and probe pathways involving bioactive lipids.

 

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Sphingolipids represent one of the major classes of eukaryotic lipids. Historically, the first sphingolipids were isolated from brain in the late 19th century by Thudicum, who introduced the name ‘sphingosin’ after the Greek mythical creature, the Sphinx, in deference to “the many enigmas which it presented to the inquirer”.

Biochemical and chemical approaches in the first part of the 20th century resulted in elucidation of the chemical structure of sphingosine, one of the major sphingoid bases, which are the founding blocks of all sphingolipids (distinguishing sphingolipids from other lipids). This discovery was followed by elucidation of the classes of complex sphingolipids (sphingomyelins and glycosphingolipids, including the gangliosides), which were appreciated as components of the plasma membrane and as modulators of cell–cell interactions and cell recognition. Concomitantly, sphingolipidoses — that is, defects in the metabolism of sphingolipids — were discovered as lysosomal storage disorders in humans.

Studies in the mid 1980s defined bioactive functions for sphingosine, followed by ceramide and S1P [sphingosine-1-phosphate].

all key enzymes in sphingolipid metabolism have now been molecularly identified, which has revealed the vast complexity of these metabolic pathways and their precise subcellular compartmentalization.

 

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Our understanding of the mechanisms of action of bioactive sphingolipids is rather sparse. S1P has been the most studied bioactive sphingolipid. S1P is mostly secreted from cells and binds to one of five S1PRs, which are G protein-coupled receptors (GPCRs)37 . These receptors then mediate all known extracellular actions of S1P through canonical GPCR signalling pathways. S1P can also act intracellularly, where it binds to histone deacetylases (HDACs), inhibiting their activity and thereby modulating histone acetylation.

More recently, c activated phosphatases have been shown to mediate the effects of palmitate on vascular endothelial growth factor signalling, possibly by interfering with activation of endothelial nitric oxide synthase.

The plethora of functions now attributed to bioactive sphingolipids is immense and touches almost all major aspects of cell biology, including roles in cell growth, the cell cycle, cell death, cell senescence, inflammation, immune responses, cell adhesion and migration, angiogenesis, nutrient uptake, metabolism, responses to stress stimuli and autophagy.

Sphingolipid metabolism has been shown to affect membrane organization and dynamics, as well as vesicular transport

Substantial literature supports the existence of specialized membrane domains, especially in the plasma membrane, which are enriched in specific lipid species, including sphingolipids (with an important contribution of ceramides). Although the precise nature and function of these domains, which also include rafts, are still not clear, they could have important roles in regulating the function of membrane receptors.

Suggesting the role of sphingolipids in membrane dynamics and signalling more broadly, a landmark study identified a role for nSMase and the resultant ceramide in the formation and secretion of exosomes, a specific subtype of secreted vesicles that have been implicated in cell–cell signalling and communication. Subsequently, several studies have disclosed that inhibition of nSMase2 can interfere with the cargo composition of these vesicles, including microRNA (miRNA).

 

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Autophagy has recently emerged as a highly regulated process in which sphingolipids are importantly involved. Ceramides regulate both cell survival and cell deathlinked autophagy by regulating nutrient transporters, ER stress and mitophagy.

A strong case for S1P in the function of the immune system has been established.

a specific pool of S1P bound to highdensity lipoprotein (HDL) has been shown to regulate lymphopoiesis and neuroinflammation not only by regulating delivery of S1P to the blood but also by modulating its receptor signalling pathways.

Ongoing studies also suggest roles for aSMase in sustaining inflammation through the production of inflammatory cytokines, especially interleukin6 (IL6) and CC chemokine ligand 5 (CCL5) in response to the action of tumour necrosis factor (TNF) and IL1.

In support of the role of ER stress in mediating these metabolic effects of S1P, cell based studies have demonstrated involvement of S1P signalling in regulating heat shock proteins, the unfolded protein response in the ER and ER stress.

 

[SNT Gatchaman]

The extent to which mammalian cells have evolved the network of bioactive sphingolipids to control many critical cellular and organismal functions is remarkable. The complexity of this network makes sphingolipids extremely difficult to study, particularly in the context of the entire organism, where specific functions in individual tissues and organs crosstalk and converge.