Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

Merrill, Alfred H.

doi:10.1021/cr2002917

Cited by 649 publications

(663 citation statements)

References 643 publications

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“…Thus, insight into S1P metabolism and how this regulates its functional activity is of key importance in understanding the role of S1P in biology and disease. S1P is produced by the sphingosine kinase-dependent phosphorylation of sphingosine, which is created as a degradation product of ceramide (4). Within cells, S1P is degraded through two pathways, either by irreversible cleavage by S1P lyase (5) or by dephosphorylation by specific S1P phosphatases (SPPases) (also known as S1P phosphohydrolases) (6).…”

Section: Sphingosine 1-phosphate (S1p)mentioning

confidence: 99%

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Taguchi¹,

Allende²,

Mizukami

et al. 2016

Journal of Biological Chemistry

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Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates basic cell functions through metabolic and signaling pathways. Intracellular metabolism of S1P is controlled, in part, by two homologous S1P phosphatases (SPPases), 1 and 2, which are encoded by the Sgpp1 and Sgpp2 genes, respectively. SPPase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. SPPase 1 is important for skin homeostasis, but little is known about the functional role of SPPase 2. To identify the functions of SPPase 2 in vivo, we studied mice with the Sgpp2 gene deleted. In contrast to Sgpp1 ؊/؊ mice, Sgpp2 ؊/؊ mice had normal skin and were viable into adulthood. Unexpectedly, WT mice expressed Sgpp2 mRNA at high levels in pancreatic islets when compared with other tissues. Sgpp2 ؊/؊ mice had normal pancreatic islet size; however, they exhibited defective adaptive ␤-cell proliferation that was demonstrated after treatment with either a high-fat diet or the ␤-cell-specific toxin, streptozotocin. Importantly, ␤-cells from untreated Sgpp2 ؊/؊ mice showed significantly increased expression of proteins characteristic of the endoplasmic reticulum stress response compared with ␤-cells from WT mice, indicating a basal islet defect. Our results show that Sgpp2 deletion causes ␤-cell endoplasmic reticulum stress, which is a known cause of ␤-cell dysfunction, and reveal a juncture in the sphingolipid recycling pathway that could impact the development of diabetes.Sphingosine 1-phosphate (S1P) 3 is a potent bioactive lipid produced from the degradation of plasma membrane sphingolipids (1-3). As a signaling molecule, S1P exerts effects in a variety of biological processes through interactions with both extracellular receptors and intracellular targets. As an intracellular metabolic intermediate, S1P is readily metabolized to other bioactive sphingolipids, such as ceramide and sphingosine, as well as to other lipids (Fig. 1A). S1P and its metabolites control basic cell functions, such as proliferation, apoptosis, and migration, and are involved in several pathologic conditions, including inflammation, metabolic disease, and cancer (1, 2). Thus, insight into S1P metabolism and how this regulates its functional activity is of key importance in understanding the role of S1P in biology and disease. S1P is produced by the sphingosine kinase-dependent phosphorylation of sphingosine, which is created as a degradation product of ceramide (4). Within cells, S1P is degraded through two pathways, either by irreversible cleavage by S1P lyase (5) or by dephosphorylation by specific S1P phosphatases (SPPases) (also known as S1P phosphohydrolases) (6). When cleaved by S1P lyase (Sgpl1), phosphoethanolamine and hexadecenal are produced, which are then transferred as substrates from the sphingolipid pathway to the glycerophospholipid pathway.In an alternative catabolic route catalyzed by S1P phosphatases, the resulting sphingosine product can be derivatized with a fatty acid by ceramide synthase to produce cer...

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Section: Sphingosine 1-phosphate (S1p)mentioning

confidence: 99%

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Taguchi¹,

Allende²,

Mizukami

et al. 2016

Journal of Biological Chemistry

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“…Their synthesis therefore depends on dedicated enzymes that are essential for viability in organisms ranging from fungi to mammals (for a review, see Gault et al 2010;Merrill 2011). The production of sphingolipids begins in the ER, where two key precursors, LCBs, and very-long-chain fatty acids (VLCFAs) are produced ( Figs.…”

Section: Sphingolipid Biosynthesismentioning

confidence: 99%

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

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“…LCBs can differ in their degree of saturation (e.g., sphingosine vs. dihydrosphingosine/ sphinganine) or hydroxylation (e.g., sphingosine vs. phytosphingosine) (2). LCBs and their phosphorylated derivatives are potent signaling molecules (3).…”

mentioning

confidence: 99%

“…The fatty acyl chain of ceramide can also vary in chain lengths, saturation, and hydroxylation (2). Emerging evidence suggests specific functions for different ceramide species.…”

mentioning

confidence: 99%

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Spassieva

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Sphingolipids exhibit extreme functional and chemical diversity that is in part determined by their hydrophobic moiety, ceramide. In mammals, the fatty acyl chain length variation of ceramides is determined by six (dihydro)ceramide synthase (CerS) isoforms. Previously, we and others showed that mutations in the major neuron-specific CerS1, which synthesizes 18-carbon fatty acyl (C 18 ) ceramide, cause elevation of long-chain base (LCB) substrates and decrease in C 18 ceramide and derivatives in the brain, leading to neurodegeneration in mice and myoclonus epilepsy with dementia in humans. Whether LCB elevation or C 18 ceramide reduction leads to neurodegeneration is unclear. Here, we ectopically expressed CerS2, a nonneuronal CerS producing C 22 -C 24 ceramides, in neurons of Cers1-deficient mice. Surprisingly, the Cers1 mutant pathology was almost completely suppressed. Because CerS2 cannot replenish C 18 ceramide, the rescue is likely a result of LCB reduction. Consistent with this hypothesis, we found that only LCBs, the substrates common for all of the CerS isoforms, but not ceramides and complex sphingolipids, were restored to the wild-type levels in the Cers2-rescued Cers1 mutant mouse brains. Furthermore, LCBs induced neurite fragmentation in cultured neurons at concentrations corresponding to the elevated levels in the CerS1-deficient brain. The strong association of LCB levels with neuronal survival both in vivo and in vitro suggests high-level accumulation of LCBs is a possible underlying cause of the CerS1 deficiency-induced neuronal death.sphingolipid | ceramide synthase | ceramide | long-chain base | neurodegeneration S phingolipids carry out essential functions in eukaryotes (1).The hydrophobic moiety of sphingolipids, called ceramide, is a fatty acylated long-chain base (LCB). LCBs can differ in their degree of saturation (e.g., sphingosine vs. dihydrosphingosine/ sphinganine) or hydroxylation (e.g., sphingosine vs. phytosphingosine) (2). LCBs and their phosphorylated derivatives are potent signaling molecules (3). Moreover, accumulation of aberrant deoxy-LCBs has recently been linked to hereditary sensory and autonomic neuropathy type 1 and taxane-induced peripheral neuropathy (4-6). Very high concentrations (100 μM) of regular LCBs are also toxic to cultured neurons (7,8). In addition, intoxication with fumonisin B1, a fungal ceramide synthase inhibitor causing elevation of LCBs and reduction of ceramides, leads to neural tube and neurological defects in humans and cattle (9). However, whether accumulation of regular LCBs in vivo or LCB treatment at physiologically relevant concentrations in vitro causes neuron death or damage has not been thoroughly investigated.The fatty acyl chain of ceramide can also vary in chain lengths, saturation, and hydroxylation (2). Emerging evidence suggests specific functions for different ceramide species. For instance, ceramide with a C 18 fatty acyl chain (C 18 ceramide) has been suggested to cause apoptosis in certain cancer cells, whereas ceramide with a C 16 ...

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Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

Cited by 649 publications

References 643 publications

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

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