Characterization of Ceramide Synthase 2

Laviad, Elad L.; Albee, Lee D.; Pankova-Kholmyansky, Irene; Epstein, Sharon; Park, Hye-Jung; Merrill, Alfred H.; Futerman, Anthony H.

doi:10.1074/jbc.m707386200

Cited by 415 publications

(191 citation statements)

References 35 publications

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“…2009), a subspecies produced by hepatic ceramide synthase 2 (Laviad et al. 2008) and exported within liver‐derived lipoproteins (Lightle et al. 2003; Boon et al.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

et al. 2017

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The 2010 USDA Dietary Guidelines for Americans (DGA) recommends a diet largely composed of fruit and vegetables. Consuming a diet high in fruit and vegetables and low in refined carbohydrates and saturated fat may reduce an individual's risk for type 2 diabetes, nonalcoholic fatty liver disease, low‐grade chronic inflammation, and metabolic syndrome (MetS). Several recent studies have implicated the bioactive sphingolipid ceramide as an associative and causative biomarker for the development of these conditions. Considering that the intake of fruit and vegetables is frequently inadequate in young adults, we performed a pilot investigation to assess the efficacy of a free‐living fruit and vegetable intervention on overall metabolic health, circulating ceramide supply, and inflammatory status in young adults. We discovered that adoption of the recommended DGA for fruit and vegetable intake for 8 weeks decreased waist circumference, systolic blood pressure, and circulating cholesterol. Lipidomics analysis revealed that nutritional intervention can lower circulating ceramides, including C24:0 ceramide, a known inhibitor of insulin signaling. Unexpectedly, we observed an increase in C16:0 ceramide, suggesting that this form of ceramide in circulation is not associated with metabolic disease in humans. We also observed an improved inflammatory status with enhanced fruit and vegetable intake that was correlated with ceramide concentrations. These data suggest that adopting the recommended DGA is associated with a reduction of many, but not all, ceramide species and may help to prevent or mitigate MetS. Future research needs to assess whether the ceramide‐lowering ability of nutritional intervention is associated with reduced risk of developing metabolic disease.

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“…2009), a subspecies produced by hepatic ceramide synthase 2 (Laviad et al. 2008) and exported within liver‐derived lipoproteins (Lightle et al. 2003; Boon et al.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

et al. 2017

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“…Lipid Biochemistry-CerS activity was assayed using [ 3 H]sphinganine and acyl-CoAs of different chain lengths (15,19) using 150 g of protein.…”

Section: Materials-d-erythro-mentioning

confidence: 99%

“…CerS2 can utilize a wider range of fatty acyl-CoAs but uses mainly C22 to C24. In addition, CerS2 displays complex modes of regulation and has genomic features characteristic of a "housekeeping" gene, although no other CerS genes display these characteristics (15).…”

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confidence: 99%

A Critical Role for Ceramide Synthase 2 in Liver Homeostasis

Pewzner-Jung

Park

Laviad

et al. 2010

Journal of Biological Chemistry

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Ceramide is an important lipid signaling molecule that plays critical roles in regulating cell behavior. Ceramide synthesis is surprisingly complex and is orchestrated by six mammalian ceramide synthases, each of which produces ceramides with restricted acyl chain lengths. We have generated a CerS2 null mouse and characterized the changes in the long chain base and sphingolipid composition of livers from these mice. Ceramide and downstream sphingolipids were devoid of very long (C22-C24) acyl chains, consistent with the substrate specificity of CerS2 toward acyl-CoAs. Unexpectedly, C16-ceramide levels were elevated, and as a result, total ceramide levels were unaltered; however, C16-ceramide synthesis in vitro was not increased. Levels of sphinganine were also significantly elevated, by up to 50-fold, reminiscent of the effect of the ceramide synthase inhibitor, fumonisin B1. With the exceptions of glucosylceramide synthase and neutral sphingomyelinase 2, none of the other enzymes tested in either the sphingolipid biosynthetic or degradative pathways were significantly changed. Total glycerophospholipid and cholesterol levels were unaltered, although there was a marked elevation in C18:1 and C18:2 fatty acids in phosphatidylethanolamine, concomitant with a reduction in C18:0 and C20:4 fatty acids. Finally, differences were observed in the biophysical properties of lipid extracts isolated from liver microsomes, with membranes from CerS2 null mice displaying higher membrane fluidity and showing morphological changes. Together, these results demonstrate novel modes of cross-talk and regulation between the various branches of lipid metabolic pathways upon inhibition of very long acyl chain ceramide synthesis.Biological membranes contain thousands of different lipid species that can be broadly classified according to their backbone structure (1). Of these, sphingolipids (SL) 2 have become particularly prominent due to the discovery of their unexpected structural complexity and their intricate modes of cellular trafficking and metabolism (2-4). Ceramides are perhaps the most well studied class of SLs, because of their essential roles in differentiation and in apoptosis (5-7). Ceramides can differ in both their long chain sphingoid base (8) and fatty acid composition (9). Over the past few years, a complex mode of regulation of ceramide synthesis has been described, with each of the six mammalian ceramide synthase (CerS) (formerly known as Lass (longevity assurance)) genes generating ceramides with specific acyl chain lengths (10). Thus, CerS1 uses mostly C18-CoA (11); CerS4 uses C18-and C20-CoAs (12); CerS5 and CerS6 use mostly C16-CoA (12, 13); and CerS3 uses very long chain acyl-CoAs (C26 and higher) (14). CerS2 can utilize a wider range of fatty acyl-CoAs but uses mainly C22 to C24. In addition, CerS2 displays complex modes of regulation and has genomic features characteristic of a "housekeeping" gene, although no other CerS genes display these characteristics (15).We have now generated a CerS2 null mouse and have ...

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“…K Ca 1.1 upregulation by CerS2 knockdown suggests that CerS2 negatively contributes to K Ca 1.1 expression, and an inhibitory effect of S1P on CerS2 activity (Laviad et al ., 2008) suggests that S1P upregulates K Ca 1.1 by inhibiting CerS2. In addition, K Ca 1.1 upregulation by CerS5 transfection suggests that CerS5 positively contributes to K Ca 1.1 expression.…”

Section: Discussionmentioning

confidence: 99%

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaK_C_a1.1 upregulation

Choi

Kim

et al. 2015

Aging Cell

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Summary KC a1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in KC a1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids (SLs) are important structural components of cellular membranes whose altered composition may affect KC a1.1 expression. Thus, in this study, we examined whether altered SL composition due to aging may affect the contractility of gastric smooth muscle (GSM). We studied changes in ceramide synthases (CerS) and SL levels in the GSM of mice of varying ages and compared them with those in young CerS2‐null mice. The levels of C16‐ and C18‐ceramides, sphinganine, sphingosine, and sphingosine 1‐phosphate were increased, and levels of C22, C24:1 and C24 ceramides were decreased in the GSM of both aged wild‐type and young CerS2‐null mice. The altered SL composition upregulated KC a1.1 and increased KC a1.1 currents, while no change was observed in KC a1.1 channel activity. The upregulation of KC a1.1 impaired intracellular 2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C ζ, c‐Jun N‐terminal kinases, and nuclear factor kappa‐B were found to be involved in KC a1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or CerS2 ablation upregulate KC a1.1 via the phosphoinositide 3‐kinase/protein kinase C ζ/c‐Jun N‐terminal kinases/nuclear factor kappa‐B‐mediated pathway and impair 2+ mobilization, which thereby induces the contractile dysfunction of GSM. CerS2‐null mice exhibited similar effects to aged wild‐type mice; therefore, CerS2‐null mouse models may be utilized for investigating the pathogenesis of aging‐associated motility disorders.

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Characterization of Ceramide Synthase 2

Cited by 415 publications

References 35 publications

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

A Critical Role for Ceramide Synthase 2 in Liver Homeostasis

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaK_C_a1.1 upregulation

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Characterization of Ceramide Synthase 2

Cited by 415 publications

References 35 publications

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

A Critical Role for Ceramide Synthase 2 in Liver Homeostasis

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaKCa1.1 upregulation

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Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle viaK_C_a1.1 upregulation