Limits...
Involvement of sphingolipids in ethanol neurotoxicity in the developing brain.

Saito M, Saito M - Brain Sci (2013)

Bottom Line: The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation.While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis.Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, USA. marsaito@nki.rfmh.org.

ABSTRACT
Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation. Such apoptotic pathways are often mediated by sphingolipids, a class of bioactive lipids ubiquitously present in eukaryotic cellular membranes. While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that ethanol-induced neuronal apoptosis in animal models of FASD is mediated or regulated by cellular sphingolipids, including via the pro-apoptotic action of ceramide and through the neuroprotective action of GM1 ganglioside. Such sphingolipid involvement in ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against FASD. Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate.

No MeSH data available.


Related in: MedlinePlus

Ceramide generating pathways. Three major pathways for ceramide generation are shown here. Ceramide is synthesized via “de novo synthesis pathway” in endoplasmic reticulum (ER), which involves several enzymes including serine palmitoyltransferase (SPT, the initial sphingolipid synthesizing enzyme) and ceramide synthase (CerS). Ceramide can be generated by activation of neutral (n) or acid (a) SMases (“SMase pathway”), often found in the plasma membrane. In the “salvage pathway”, ceramide is synthesized by CerS from sphingosine released from the lysosome. Although not shown here, ceramide generation may also occur in the mitochondria, where ceramide generating enzymes, such as CerS, have been found. These pathways are activated by a variety of apoptotic inducers in various cell types including neurons as described in the text. (CDase, ceramidase; SphK, sphingosine kinase; SPPase, S1P phosphatase; GCS, glucosylceramide synthase; SMS, sphingomyelin synthase; GlcCer, glucosylceramide.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4061845&req=5

brainsci-03-00670-f001: Ceramide generating pathways. Three major pathways for ceramide generation are shown here. Ceramide is synthesized via “de novo synthesis pathway” in endoplasmic reticulum (ER), which involves several enzymes including serine palmitoyltransferase (SPT, the initial sphingolipid synthesizing enzyme) and ceramide synthase (CerS). Ceramide can be generated by activation of neutral (n) or acid (a) SMases (“SMase pathway”), often found in the plasma membrane. In the “salvage pathway”, ceramide is synthesized by CerS from sphingosine released from the lysosome. Although not shown here, ceramide generation may also occur in the mitochondria, where ceramide generating enzymes, such as CerS, have been found. These pathways are activated by a variety of apoptotic inducers in various cell types including neurons as described in the text. (CDase, ceramidase; SphK, sphingosine kinase; SPPase, S1P phosphatase; GCS, glucosylceramide synthase; SMS, sphingomyelin synthase; GlcCer, glucosylceramide.)

Mentions: Ceramides are essential sphingolipid messengers regulating a diverse range of cell-stress responses, such as apoptosis, cell senescence, and autophagy. Various factors, including the species of ceramides generated (out of >200 structurally distinct molecules) and its subcellular localization, appear to determine the ceramide functions (reviewed by [117]). Numerous studies have demonstrated that ceramide mediates or enhances both extrinsic and intrinsic apoptotic pathways in many cell types (reviewed by [1,2,3,118]) including neurons (reviewed by [8,9,10,11,12,119,120]). While such ceramide-mediated apoptosis can be beneficial during a certain period of neuronal development for regulating neural cell numbers [14,15,17,121], dysregulated ceramide formation is implicated in neural death in several neuroinflammatory and neurodegenerative disorders (reviewed by [8,11,12,18,19,20]). A variety of studies using cultured neurons and animal models of neurodegenerative diseases support the notion that ceramide is involved in the apoptotic pathways (reviewed by [8,9,10,11,12,119,120,122]). First, cellular ceramide elevation, either by adding natural or short-acyl chain analogs of ceramide or by modulating ceramide metabolizing enzymes, induces apoptosis in cultured neurons (reviewed by [11,119,122]). Second, many apoptotic inducers elevate endogenous levels of ceramide, and the inhibition of such ceramide generation by pharmacological or genetic manipulation attenuates cell death (reviewed by [8,11,12,20,119,120]). As shown in Figure 1, ceramide can be generated by activation of neutral or acid sphingomyelinase (SMase), by activation of the salvage pathway, which involves ceramide formation from sphingosine released from the lysosome, or by enhancement of de novo ceramide synthesis (reviewed by [2,4,11,20,120]). In general, neutral and acidic SMases trigger early and transient ceramide increase, while de novo ceramide synthesis causes late and sustained ceramide elevation [123]. Recent studies indicate that molecular species of ceramides thus produced is an important factor in determining ceramide functions [117]. In untreated cultured neurons, C18 is a major fatty acid of ceramides [124], and ceramide synthase 1 (CerS1) that catalyzes de novo synthesis of C18 ceramide is a major and specific CerS in neurons [125] out of six mammalian CerSs (CerS1–CerS6) (reviewed by [126]). However, the increase in C16 ceramide is associated with apoptosis in neurons [124,127,128] as well as in some other cell types [129,130,131], while increases in C20 and C24 ceramides in hippocampal tissues from an Alzheimer’s disease (AD) mouse model are linked to astroglial cell death [132].


Involvement of sphingolipids in ethanol neurotoxicity in the developing brain.

Saito M, Saito M - Brain Sci (2013)

Ceramide generating pathways. Three major pathways for ceramide generation are shown here. Ceramide is synthesized via “de novo synthesis pathway” in endoplasmic reticulum (ER), which involves several enzymes including serine palmitoyltransferase (SPT, the initial sphingolipid synthesizing enzyme) and ceramide synthase (CerS). Ceramide can be generated by activation of neutral (n) or acid (a) SMases (“SMase pathway”), often found in the plasma membrane. In the “salvage pathway”, ceramide is synthesized by CerS from sphingosine released from the lysosome. Although not shown here, ceramide generation may also occur in the mitochondria, where ceramide generating enzymes, such as CerS, have been found. These pathways are activated by a variety of apoptotic inducers in various cell types including neurons as described in the text. (CDase, ceramidase; SphK, sphingosine kinase; SPPase, S1P phosphatase; GCS, glucosylceramide synthase; SMS, sphingomyelin synthase; GlcCer, glucosylceramide.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061845&req=5

brainsci-03-00670-f001: Ceramide generating pathways. Three major pathways for ceramide generation are shown here. Ceramide is synthesized via “de novo synthesis pathway” in endoplasmic reticulum (ER), which involves several enzymes including serine palmitoyltransferase (SPT, the initial sphingolipid synthesizing enzyme) and ceramide synthase (CerS). Ceramide can be generated by activation of neutral (n) or acid (a) SMases (“SMase pathway”), often found in the plasma membrane. In the “salvage pathway”, ceramide is synthesized by CerS from sphingosine released from the lysosome. Although not shown here, ceramide generation may also occur in the mitochondria, where ceramide generating enzymes, such as CerS, have been found. These pathways are activated by a variety of apoptotic inducers in various cell types including neurons as described in the text. (CDase, ceramidase; SphK, sphingosine kinase; SPPase, S1P phosphatase; GCS, glucosylceramide synthase; SMS, sphingomyelin synthase; GlcCer, glucosylceramide.)
Mentions: Ceramides are essential sphingolipid messengers regulating a diverse range of cell-stress responses, such as apoptosis, cell senescence, and autophagy. Various factors, including the species of ceramides generated (out of >200 structurally distinct molecules) and its subcellular localization, appear to determine the ceramide functions (reviewed by [117]). Numerous studies have demonstrated that ceramide mediates or enhances both extrinsic and intrinsic apoptotic pathways in many cell types (reviewed by [1,2,3,118]) including neurons (reviewed by [8,9,10,11,12,119,120]). While such ceramide-mediated apoptosis can be beneficial during a certain period of neuronal development for regulating neural cell numbers [14,15,17,121], dysregulated ceramide formation is implicated in neural death in several neuroinflammatory and neurodegenerative disorders (reviewed by [8,11,12,18,19,20]). A variety of studies using cultured neurons and animal models of neurodegenerative diseases support the notion that ceramide is involved in the apoptotic pathways (reviewed by [8,9,10,11,12,119,120,122]). First, cellular ceramide elevation, either by adding natural or short-acyl chain analogs of ceramide or by modulating ceramide metabolizing enzymes, induces apoptosis in cultured neurons (reviewed by [11,119,122]). Second, many apoptotic inducers elevate endogenous levels of ceramide, and the inhibition of such ceramide generation by pharmacological or genetic manipulation attenuates cell death (reviewed by [8,11,12,20,119,120]). As shown in Figure 1, ceramide can be generated by activation of neutral or acid sphingomyelinase (SMase), by activation of the salvage pathway, which involves ceramide formation from sphingosine released from the lysosome, or by enhancement of de novo ceramide synthesis (reviewed by [2,4,11,20,120]). In general, neutral and acidic SMases trigger early and transient ceramide increase, while de novo ceramide synthesis causes late and sustained ceramide elevation [123]. Recent studies indicate that molecular species of ceramides thus produced is an important factor in determining ceramide functions [117]. In untreated cultured neurons, C18 is a major fatty acid of ceramides [124], and ceramide synthase 1 (CerS1) that catalyzes de novo synthesis of C18 ceramide is a major and specific CerS in neurons [125] out of six mammalian CerSs (CerS1–CerS6) (reviewed by [126]). However, the increase in C16 ceramide is associated with apoptosis in neurons [124,127,128] as well as in some other cell types [129,130,131], while increases in C20 and C24 ceramides in hippocampal tissues from an Alzheimer’s disease (AD) mouse model are linked to astroglial cell death [132].

Bottom Line: The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation.While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis.Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, USA. marsaito@nki.rfmh.org.

ABSTRACT
Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation. Such apoptotic pathways are often mediated by sphingolipids, a class of bioactive lipids ubiquitously present in eukaryotic cellular membranes. While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that ethanol-induced neuronal apoptosis in animal models of FASD is mediated or regulated by cellular sphingolipids, including via the pro-apoptotic action of ceramide and through the neuroprotective action of GM1 ganglioside. Such sphingolipid involvement in ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against FASD. Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate.

No MeSH data available.


Related in: MedlinePlus