Ceramides as modulators of cellular and whole-body metabolism

Bikman, Benjamin T.; Summers, Scott A.

doi:10.1172/jci57144

Cited by 352 publications

(301 citation statements)

References 137 publications

(152 reference statements)

Supporting

Mentioning

285

Contrasting

Unclassified

Order By: Relevance

“…Accumulation of GlcCer could also affect the concentration of upstream sphingolipids such as ceramide (Fig. S4), known to affect cell growth (36). However, targeted down-regulation of the GlcCer synthase by RNA interference experiments cause apoptotic cell death in Drosophila (37), indicating that it is unlikely that the observed nerve phenotype is due to increased concentrations of ceramide or other upstream biosynthetic intermediates.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

Dahlgaard¹,

Jung

Qvortrup

et al. 2012

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

View full text Add to dashboard Cite

Glycosphingolipids (GSLs) are of fundamental importance in the nervous system. However, the molecular details associated with GSL function are largely unknown, in part because of the complexity of GSL biosynthesis in vertebrates. In Drosophila , only one major GSL biosynthetic pathway exists, controlled by the glycosyltransferase Egghead (Egh). Here we discovered that loss of Egh causes overgrowth of peripheral nerves and attraction of immune cells to the nerves. This phenotype is reminiscent of the human disorder neurofibromatosis type 1, which is characterized by disfiguring nerve sheath tumors with mast cell infiltration, increased cancer risk, and learning deficits. Neurofibromatosis type 1 is due to a reduction of the tumor suppressor neurofibromin, a negative regulator of the small GTPase Ras. Enhanced Ras signaling promotes glial growth through activation of phosphatidylinositol 3-kinase (PI3K) and its downstream kinase Akt. We find that overgrowth of peripheral nerves in egh mutants is suppressed by down-regulation of the PI3K signaling pathway by expression of either dominant-negative PI3K, the tumor suppressor PTEN, or the transcription factor FOXO in the subperineurial glia. These results show that loss of the glycosyltransferase Egh affects membrane signaling and activation of PI3K signaling in glia of the peripheral nervous system, and suggest that glycosyltransferases may suppress proliferation.

show abstract

Section: Discussionmentioning

confidence: 99%

Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

Dahlgaard¹,

Jung

Qvortrup

et al. 2012

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

View full text Add to dashboard Cite

show abstract

“…PPARα maintains the constitutive expression of genes for several enzymes that are involved in the mitochondrial fatty acid β-oxidation system, such as long-chain acyl-CoA synthetase, and PPARα activation induces gene expression of these enzymes and stimulates β-oxidation [11, [38][39][40][41][42][43]. Because the synthesis of sphingolipids is initiated by the transfer of L-serine onto activated long-chain fatty acids, such as palmitoyl-CoA, which arises from the reaction with long-chain acyl-CoA synthetase [44], PPARα presumably participates in the regulation of overall sphingolipid metabolism. In fact, a previous study has shown ceramide accumulation in human skin cells that are treated with the potent PPARα agonist Wy-14,643, together with increases in gene expression and activity of serine palmitoyltransferase [45], which is the key enzyme for the initial step in sphingolipid synthesis [46].…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

et al. 2012

View full text Add to dashboard Cite

Sulfatides, 3-O-sulfogalactosylceramides, are known to have multifunctional properties. These molecules are distributed in various tissues of mammals, where they are synthesized from galactosylceramides by sulfation at C3 of the galactosyl residue.Although this reaction is specifically catalyzed by cerebroside sulfotransferase (CST), the mechanisms underlying the transcriptional regulation of this enzyme are not understood. With respect to this issue, we previously found potential sequences of peroxisome proliferator-activated receptor (PPAR) response element on upstream regions of the mouse CST gene and presumed the possible regulation by the nuclear receptor PPARα. To confirm this hypothesis, we treated wild-type and Ppara-null mice with the specific PPARα agonist fenofibrate and examined the amounts of sulfatides and CST gene expression in various tissues. Fenofibrate treatment increased sulfatides and CST mRNA levels in the kidney, heart, liver, and small intestine in a PPARα-dependent manner. However, these effects of fenofibrate were absent in the brain or colon.Fenofibrate treatment did not affect the mRNA level of arylsulfatase A, which is the key enzyme for catalyzing desulfation of sulfatides, in any of these six tissues. Analyses of the DNA-binding activity and conventional gene expression targets of PPARα has demonstrated that fenofibrate treatment activated PPARα in the kidney, heart, liver, and 4 small intestine but did not affect the brain or colon. These findings suggest that PPARα activation induces CST gene expression and enhances sulfatide synthesis in mice, which suggests that PPARα is a possible transcriptional regulator for the mouse CST gene.(less than 250 words)

show abstract

“…Circulating and cellular S1P concentrations are regulated by the synthesis and catabolism of S1P (15,30,43). The availability of Sph is a key event in the intracellular generation of S1P, and Sph is derived either from ceramides through ceramidases or from circulating plasma S1P through ecto-LPPs (9,17,18). Recent studies showed that human lung ECs have the ability to use exogenously added S1P to generate intracellular S1P by lipid phosphate phosphatases (18).…”

Section: Sphingosine Kinases and S1p Lyase In Sepsis-induced Lung Injurymentioning

confidence: 99%

“…Since their initial description, sphingoid bases have been found to be critical structural components of biological membranes and highly essential bioactive lipids that regulate diverse signaling pathways. The aberrant regulation of the sphingoid bases is known to contribute to a variety of pathologies that underlie cancer, inflammation, injury, edema, and infections (5)(6)(7)(8)(9). Of the several hundred sphingoid bases described to date, at least six, namely, sphingomyelin (SM), sphingosine (Sph), Sph-1-phosphate (S1P), ceramide, ceramide 1-phosphate (Cer1P), and sphingosylphosphorylcholine (lyso-SM), are considered key signaling and regulatory bioactive lipids (10).…”

mentioning

confidence: 99%

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

Natarajan

Dudek

Jacobson

et al. 2013

Am J Respir Cell Mol Biol

124

131

View full text Add to dashboard Cite

Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P 1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.Keywords: sphingolipids; S1P receptors; sphingosine kinase; S1P lyase; sepsis Acute and subacute inflammatory lung injuries are common and devastating disorders resulting from insults such as sepsis, ventilator-induced lung injury, ischemia/reperfusion, hyperoxia, and radiation therapy for thoracic malignancies. Unfortunately, despite recent advances in our understanding of the mechanisms and pathophysiology of acute lung injury (ALI), mortality rates remain very high (30-50%) because of the dearth of specific therapies for the treatment of ALI (1, 2). The only therapy for radiation-induced pneumonitis is based on long-term treatment with a high dose of corticosteroids. However, it is encumbered by severe side effects and relatively low efficacy (3). Therefore, an urgent need exists for new mechanistic insights into the pathophysiology of ALI that are likely to reveal new potential therapeutic targets, discover novel biomarkers, and develop highly efficacious targeted therapies that will effectively reduce the morbidity and mortality associated with acute and subacute lung injury."Sphingosin," first described by J. L. W. Thudichum in 1884, derived its name from the Greek word "sphinx" meaning enigmatic, and it encompasses many compounds commonly referred to as "sphingoid bases" (4). Since thei...

show abstract

Ceramides as modulators of cellular and whole-body metabolism

Cited by 352 publications

References 137 publications

Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

Contact Info

Product

Resources

About