Characterization of Serine Palmitoyltransferase in Normal Human Tissues

Batheja, Ameesha; Uhlinger, David J.; Carton, Jill M.; Ho, George; D’Andrea, Michael R.

doi:10.1177/002215540305100514

Cited by 27 publications

(31 citation statements)

References 43 publications

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“…The reaction carried out by SPT - the condensation of serine and palmitoyl CoA to produce dihydrosphingosine (dhSph) - has been shown to be a rate-limiting step in de novo sphingolipid biosynthesis21. Humans possess three variants of SPT (SPTLC1, SPTLC2, SPTLC3), and SNPs in all three have been found to be significantly associated with type 2 diabetes and related phenotypes22232425262728.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic interplay between ceramide and insulin resistance

Reali

Morine

Kahramanoğulları

et al. 2017

Sci Rep

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Recent research adds to a growing body of literature on the essential role of ceramides in glucose homeostasis and insulin signaling, while the mechanistic interplay between various components of ceramide metabolism remains to be quantified. We present an extended model of C16:0 ceramide production through both the de novo synthesis and the salvage pathways. We verify our model with a combination of published models and independent experimental data. In silico experiments of the behavior of ceramide and related bioactive lipids in accordance with the observed transcriptomic changes in obese/diabetic murine macrophages at 5 and 16 weeks support the observation of insulin resistance only at the later phase. Our analysis suggests the pivotal role of ceramide synthase, serine palmitoyltransferase and dihydroceramide desaturase involved in the de novo synthesis and the salvage pathways in influencing insulin resistance versus its regulation.

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Section: Discussionmentioning

confidence: 99%

Mechanistic interplay between ceramide and insulin resistance

Reali

Morine

Kahramanoğulları

et al. 2017

Sci Rep

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“…It all starts in the endoplasmic reticulum (ER), where condensation of serine with palmitoyl-CoA generates 3-ketodihydrosphingosine (ketosphinganine) (Figure 2). This reaction is catalyzed by serine palmitoyltransferase (SPT), a membrane-resident enzyme consisting of two subunits, SPT1 (SPTLC-1) and SPT2 (SPTLC-2) [156][157][158][159][160][161][162]. Most recently, a third subunit, SPTLC-3, has been described and suggested to form a high molecular mass complex with the other two subunits [163].…”

Section: Sphingolipid Biosynthesis In the Endoplasmic Reticulum: Enzymentioning

confidence: 99%

Ceramide signaling in cancer and stem cells

Bieberich

2008

Future Lipidology

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Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of 'systems interface biology': as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-1-phosphate. Lipid rafts and sphingolipid-induced protein scaffolds will be discussed as a membrane interface for lipid-controlled cell signaling. Ceramide/sphingomyelin and ceramide/ sphingosine-1-phosphate-interdependent cell-signaling pathways are significant for the regulation of cell polarity, apoptosis and/or proliferation, and as novel pharmacologic targets in cancer and stem cells. Keywordsapoptosis; cancer; cell polarity; ceramide; ES cells; lipid rafts; sphingomyelin; sphingosine-1-phosphate Ceramide & its derivatives: from metabolism to cell signalingThe structural core of ceramide is the sphingoid base sphingosine (Figure 1), a lipid that is synthesized from the amino acid serine and the activated fatty acid palmitoyl-CoA (Figure 2). Sphingosine (or sphingenine) was first isolated and characterized by the German pathologist and 'father of neurochemistry ' Johann Ludwig Wilhelm Thudichum (1829-1901 [1,2]. He coined the term sphingolipids, which is derived from 'sphingos', the genitive of Sphinx. In Greek, 'sphingo' means 'to strangle'. According to the legend, a fate of death was meant for everyone who could not solve the riddles posed by the Sphinx. Quite ironically, this is how many sphingolipid researchers may feel when faced with analyzing the function of ceramide. The riddle of ceramide, its function and how it acts as signaling lipid, is far from being solved. To ease our fears when confronted with the Sphinx in sphingolipid biochemistry, a related Greek word, 'sphingein', meaning 'to bind tight', alludes to the possibility of solving the enigma of ceramide by identifying its binding proteins.In addition to ceramide, more than a hundred different sphingolipids are known. The most comprehensive collection of sphingolipids, with respect to their characteristics and structures, can be found at [401], a Webpage supported by the National Institutes of General Medical Sciences [3,4]. Sphingolipids are essential components of cellular membranes and have been (Figure 3) . Among these, their roles as pro-or anti-apoptotic and pro-or anti-proliferative signaling lipids are the most important. Most recently, our group has found that establishment of cell polarity during embryonic development is another biological process regulated by sphingolipids [28]. To define a profile of functions for individual sphingolipids is difficult because of their rapid metabolic interconversion. To add to this predicament, several derivatives of ceramide have functions similar to ceramide itself. Hence, novel techniques are need...

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“…The major pathway of sphingolipid synthesis occurs through recycling of long-chain sphingoid bases that are derived from the catabolism of complex sphingolipids. In contrast, de novo synthesis is not as ubiquitous and is often found to be increased in cells with a high proliferation rate (14,15). Serinepalmitoyl transferase (SPT), found in the endoplasmic reticulum, is the rate-limiting enzyme of de novo synthesis.…”

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confidence: 99%

Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling

Hamai

Keyserman

Quittell³

et al. 2009

Journal of Lipid Research

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) that affect protein structure and channel function. CFTR, localized in the apical membrane within cholesterol and sphingomyelin rich regions, is an ABC transporter that functions as a chloride channel. Here, we report that expression of defective CFTR (#F508CFTR or decreased CFTR) in human lung epithelial cell lines increases sphingolipid synthesis and mass of sphinganine, sphingosine, four long-chain saturated ceramide species, C16 dihydroceramide, C22, C24, C26-ceramide, and sphingomyelin, and decreases mass of C18 and unsaturated C18:1 ceramide species. Decreased expression of CFTR is associated with increased expression of longchain base subunit 1 of serine-palmitoyl CoA, the rate-limiting enzyme of de novo sphingolipid synthesis and increased sphingolipid synthesis. Overexpression of #F508CFTR in bronchoalveolar cells that do not express CFTR increases sphingolipid synthesis and mass, whereas overexpression of wild-type CFTR, but not of an unrelated ABC transporter, ABCA7, decreases sphingolipid synthesis and mass. The data are consistent with a model in which CFTR functions within a feedback system that affects sphingolipid synthesis and in which increased sphingolipid synthesis could reflect a physiological response to sequestration of sphingolipids or altered membrane structure.-Hamai, H., F. Keyserman, L. M. Quittell, and T. S. Worgall. Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling.

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Characterization of Serine Palmitoyltransferase in Normal Human Tissues

Cited by 27 publications

References 43 publications

Mechanistic interplay between ceramide and insulin resistance

Mechanistic interplay between ceramide and insulin resistance

Ceramide signaling in cancer and stem cells

Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling

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