The complex life of simple sphingolipids

Abstract

The extensive diversity of membrane lipids is rarely appreciated by cell and molecular biologists. Although most researchers are familiar with the three main classes of lipids in animal cell membranes, few realize the enormous combinatorial structural diversity that exists within each lipid class, a diversity that enables functional specialization of lipids. In this brief review, we focus on one class of membrane lipids, the sphingolipids, which until not long ago were thought by many to be little more than structural components of biological membranes. Recent studies have placed sphingolipidsincluding ceramide, sphingosine and sphingosine-1-phosphate-at the centre of a number of important biological processes, specifically in signal transduction pathways, in which their levels change in a highly regulated temporal and spatial manner. We outline exciting progress in the biochemistry and cell biology of sphingolipids and focus on their functional diversity. This should set the conceptual and experimental framework that will eventually lead to a fully integrated and comprehensive model of the functions of specific sphingolipids in regulating defined aspects of cell physiology. Keywords: lipids; sphingolipids; second messenger; ceramide; sphingosine-1-phosphate; raft EMBO reports (2004EMBO reports ( ) 5, 777-782. doi:10.1038 Why biologists can no longer afford to ignore lipids ''Cell membranes are crucial to the life of the cell''. Thus begins a description of the plasma membrane in one of our favourite textbooks (Alberts et al, 2002). Reading on, we learn that "lipids constitute about 50% of the mass of most animal cell membranes," and that there are "about 10 9 lipid molecules in the plasma membrane of a small animal cell." But sadly, the space devoted to further discussion of lipids in this book, and it must be said (lest the reader think that we have an axe to grind against this excellent book), in most other cell biology and biochemistry textbooks, is far less than that expected on the basis of their high abundance. Why is this? Is so much known about lipid cell biology that there is little new to discuss? Are lipids too boring to be worthy of significant attention? The answer is probably related to the perceived difficulties of working with membrane lipids and to a lack of appreciation of the essential and diverse roles that membrane lipids exert in regulating a wide spectrum of physiological events.Cell membranes and lipids are indeed crucial to the life of the cell, but as many famous and wise people have said before us, "the devil is in the details". And the details are complicated. Not only are there three main classes of lipids in cell membranes (glycerolipids, sphingolipids and sterols), but also a huge structural variety exists within each class so that hundreds of individual lipid species (and tens of thousands of subspecies) exist within each cell. Does each individual lipid species have defined functions? How are their levels maintained and regulated? How is their complex intracellular distribution ...

Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

“…Much evidence has been presented in recent years indicating that S1P is both a mitogenic and a survival factor, whereas ceramide has pro-apoptotic potential (Huwiler et al, 2000;Futerman and Hannun, 2004;Huwiler and Pfeilschifter, 2006). However, our data now suggest that this concept does not accurately reflect reality.…”

“…It is well reported in the literature that the balance of the two sphingolipids ceramide and S1P determines the cell's fate to either proliferate or undergo apoptosis (Huwiler et al, 2000;Futerman and Hannun, 2004;Huwiler and Pfeilschifter, 2006). Much evidence has been presented in recent years indicating that S1P is both a mitogenic and a survival factor, whereas ceramide has pro-apoptotic potential (Huwiler et al, 2000;Futerman and Hannun, 2004;Huwiler and Pfeilschifter, 2006).…”

“…Although sphingolipids exert their main function as structural components of cellular membranes, it has become clear that some sphingolipid species also have critical functions as signalling molecules and regulate a variety of physiological and pathophysiological processes such as cell growth and differentiation, cell migration and adhesion, and apoptosis (Huwiler et al, 2000;Futerman and Hannun, 2004;Huwiler and Pfeilschifter, 2006).…”

Sphingosine-1-phosphate and modulation of vascular tone

“…For an extensive review of biosynthesis and metabolism of sphingolipids in general, see Futerman and Hannun. 7 In brief, sphingosine kinases (SphK) catalyse the ATP-dependent phosphorylation of sphingosine to produce S1P. Thus far, two different SphK isoforms have been found in mammals named SphK-1 and SphK-2, each having distinct patterns of tissue distribution and enzymatic properties (see review 8 ).…”

Horizontal gene transfer of an entire metabolic pathway between a eukaryotic alga and its DNA virus

“…Sphingolipids are membrane lipids present in all eukaryotes, and some prokaryotes, that are involved in the regulation of various cellular processes (Futerman and Hannun 2004). Sphingolipid metabolism has been mostly studied in mammalian and yeast cells, where it was found to play key roles in signal transductions (Hannun et al 2001).…”