Kinetics of long-chain (sphingoid) base biosynthesis in intact LM cells: effects of varying the extracellular concentrations of serine and fatty acid precursors of this pathway

Merrill, Alfred H.; Wang, Elaine; Mullins, Richard E.

doi:10.1021/bi00401a051

Cited by 94 publications

(75 citation statements)

References 33 publications

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“…4 Further evidence of a cholesterol-independent regulation of SREBP is found in Drosophila melanogaster, where SREBP levels are only regulated by palmitic acid and phosphatidylcholine but not by cholesterol or unsaturated fatty acids. 42 Palmitic acid determines the rate of long-chain sphinganine synthesis, 30 which can be further metabolized to ceramide. Hence, ceramide synthesis may also contribute to SREBP regulation in Drosophila.…”

Section: Discussionmentioning

confidence: 99%

Ceramide Synthesis Correlates with the Posttranscriptional Regulation of the Sterol-Regulatory Element-Binding Protein

Worgall

Juliano

Seo

et al. 2004

ATVB

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Objective-Sterol-regulatory element-binding proteins (SREBPs) regulate transcription of genes of lipid metabolism.Ceramide decreases transcriptionally active SREBP levels independently of intracellular cholesterol levels. Mechanisms of the ceramide-mediated decrease of SREBP levels were investigated. T he sterol-regulatory element-binding proteins (SREBPs) are important transcription factors of genes of lipid metabolism. In sterol depletion, precursor SREBP is translocated from the endoplasmic reticulum by vesicular trafficking to the Golgi apparatus, 1,2 where the transcriptionally active mature SREBP is generated. Mature SREBP binds to sterolregulatory elements (SRE), cis-acting elements in the promoters of genes of cholesterol and fatty acid synthesis. 3 Cholesterol and unsaturated fatty acids are known regulators of transcriptional and posttranscriptional processing of SREBP. We recently reported that unsaturated fatty acidsmediated decreases in SRE-mediated gene transcription are linked to cellular sphingolipid metabolism. 4 Ceramide, a metabolite of sphingomyelin hydrolysis, also regulates mature SREBP levels. Regulation occurs even in the presence of inhibitors of intracellular cholesterol trafficking, suggesting a cholesterol-independent effect. 4 Ceramide has multiple roles ranging from lipid second messenger to the induction of apoptosis, cell growth, and differentiation. 5,6 Cellular ceramide levels are generated either by de novo synthesis from serine and palmitoyl-CoA or through a recycling pathway of sphingolipid hydrolysis. Methods and Results-ExperimentsCeramide also has a role in intracellular protein trafficking, can inhibit coated vesicle formation and exocytosis in Chinese hamster ovary (CHO) cells, 7 and can modulate endocytosis in mammalian cells. 8 In yeast, ongoing ceramide synthesis is critical in the vesicular ER-to-Golgi transport of GPI-anchored proteins. 9 -11 We investigated the effect of ceramide synthesis on SREBP levels and SRE-mediated gene transcription. Because increased ceramide levels decrease mature SREBP protein levels and SRE-mediated gene transcription, 4 it was anticipated that inhibition of ceramide synthesis should increase mature SREBP levels and SRE-mediated gene transcription. Contrary to this hypothesis, inhibition of ceramide synthesis decreases SRE-mediated gene transcription. Increasing ceramide synthesis correlates with increased mature SREBP levels and SRE-mediated gene transcription. Consequently, the effect of ceramide on its own synthesis was investigated and shown to be inhibitory, providing an explanation that increased ceramide levels and decreased ceramide synthesis inhibit SRE-mediated gene transcription. PlasmidsThe pSyn-SRE luciferase reporter plasmid originates from the hamster HMG-CoA synthase promoter and contains three SRE elements (Ϫ326 to Ϫ225 bp) and has been described before. 14,15 The pWLNeo plasmid was obtained from Stratagene (La Jolla, Calif). Cell Culture and Stable TransfectionsCells were grown in F12-nutrient mixture medium contai...

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Section: Discussionmentioning

confidence: 99%

Ceramide Synthesis Correlates with the Posttranscriptional Regulation of the Sterol-Regulatory Element-Binding Protein

Worgall

Juliano

Seo

et al. 2004

ATVB

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“…Ceramide can be produced from serine and palmitoyl CoA in endoplasmic reticulum (ER) via de novo synthesis (Fig. 2) [10,11]. This pathway involves several chemical reactions and separate enzymes catalyzing each step.…”

Section: Metabolism Of Sphingolipidsmentioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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“…One of the more straightforward factors that affects SPT activity is the availability of both serine-and palmitoyl-CoA, and because SPT is highly selective for fatty acyl-CoA with 16 Ϯ 1 carbon atoms, other fatty acids can be inhibitory in vivo, possibly by competing for the CoA pool (20). Serine palmitoyltransferase is inhibited by a number of synthetic and naturally occurring agents.…”

Section: De Novo Sphingolipid Biosynthesismentioning

confidence: 99%