The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani, Kazuyuki; Idkowiak‐Baldys, Jolanta; Hannun, Yusuf A.

doi:10.1016/j.cellsig.2007.12.006

Cited by 528 publications

(494 citation statements)

References 104 publications

(144 reference statements)

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“…Palmitate is a critical precursor of de novo ceramide synthesis (Kitatani et al ., 2008), which can activate apoptosis (Tohyama et al ., 1999). As such, one hypothesis to explain the enhanced sensitivity to palmitate in MDA‐MB‐231 cells compared to MCF‐7 cells was enhanced ceramide synthesis in MDA‐MB‐231 cells.…”

Section: Resultsmentioning

confidence: 99%

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

et al. 2018

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Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF‐7 and MDA‐MB‐231 cell metabolism and promotes proliferation and migration. Since adipocytes are FA‐rich, and these FAs are transferred to BrCa cells, we sought to elucidate the FA metabolism of BrCa cells and their response to FA‐rich environments. MCF‐7 and MDA‐MB‐231 cells incubated in serum‐containing media supplemented with FAs accumulate extracellular FAs as intracellular triacylglycerols (TAG) in a dose‐dependent manner, with MDA‐MB‐231 cells accumulating more TAG. The differences in TAG levels were a consequence of distinct differences in intracellular partitioning of FAs, and not due to differences in the rate of FA uptake. Specifically, MCF‐7 cells preferentially partition FAs into mitochondrial oxidation, whereas MDA‐MB‐231 cells partition FAs into TAG synthesis. These differences in intracellular FA handling underpin differences in the sensitivity to palmitate‐induced lipotoxicity, with MDA‐MB‐231 cells being highly sensitive, whereas MCF‐7 cells are partially protected. The attenuation of palmitate‐induced lipotoxicity in MCF‐7 cells was reversed by inhibition of FA oxidation. Pretreatment of MDA‐MB‐231 cells with FAs increased TAG synthesis and reduced palmitate‐induced apoptosis. Our results provide novel insight into the potential influences of obesity on BrCa biology, highlighting distinct differences in FA metabolism in MCF‐7 and MDA‐MB‐231 cells and how lipid‐rich environments modulate these effects.

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Section: Resultsmentioning

confidence: 99%

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

et al. 2018

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“…Further, the lack of histologic and morphologic evidence of lysosomal storage was suggestive that lysosomal degradation of sphingolipids was not impaired and, thus, not responsible for the elevated lipids in the lyase-deficient mice. Instead, the increased levels of sphingolipids is more compatible with their generation by the sphingolipid recycling or salvage pathway that has been shown to utilize S1P as a starting point (5,15). In the recycling pathway, S1P is dephosphorylated by S1P phosphatases, which reside in the endoplasmic reticulum, to produce sphingosine.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver

Bektas

Allende

Lee

et al. 2010

Journal of Biological Chemistry

178

200

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The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and/or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyasedeficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern, with a significant increase in the expression of PPAR␥, a master transcriptional regulator of lipid metabolism. However, the mRNA expression of the genes encoding the sphingosine kinases and S1P phosphatases, which directly control the levels of S1P, were not significantly changed in liver of the S1P lyase-deficient mice. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases.Sphingolipid metabolism generates diverse lipid molecules that are utilized by cells in multiple ways (Fig. 1A) (1, 2). Complex sphingolipids, such as sphingomyelin and glycosphingolipids, are structural components of cell membranes and drive the formation of plasma membrane lipid domains by virtue of their interactions with sterols. Metabolic intermediates, notably sphingosine, ceramide, and sphingosine-1-phosphate (S1P), 3 serve as bioactive molecules by regulating cellular signaling pathways. An additional function of sphingolipid metabolism is the synthesis of substrates that are utilized by other lipid metabolic hubs. However, the functional, regulatory, and physiological significance of the intersection of sphingolipid metabolism with other lipid pathways is not well understood.A decisive step in the sphingolipid metabolic pathway is carried out by S1P lyase, encoded by the Sgpl1 gene (3, 4). S1P lyase, which resides in the endoplasmic reticulum and is widely distributed in tissues, catalyzes the final degradative step in the sphingolipid metabolic pathway with the cleavage of phosphorylated sphingoid bases to generate phosphoethanolamine and a fatty aldehyd...

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“…This is then reduced to produce dihydrosphingosine (sphinganine), which is then acylated by dihydroceramide synthases (also known CerS) (Fig. 1) [15,17,18].…”

Section: Introductionmentioning

confidence: 99%

“…Ceramide is the central molecule in sphingolipid and glycosphingolipid biosynthesis, and there are three metabolic pathways leading to ceramide: the sphingomyelinase pathway, the de novo pathway, and the exogenous ceramide-recycling pathway [11,18]. These metabolic pathways occur in different cellular compartments [3].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Yandım

Apohan

Baran

2012

Cancer Chemother Pharmacol

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Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDPglucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

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The sphingolipid salvage pathway in ceramide metabolism and signaling

Cited by 528 publications

References 104 publications

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

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