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Review
, 56 (5), 3501-3521

The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

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Review

The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

Henryk Jęśko et al. Mol Neurobiol.

Abstract

Bioactive sphingolipids: sphingosine, sphingosine-1-phosphate (S1P), ceramide, and ceramide-1-phosphate (C1P) are increasingly implicated in cell survival, proliferation, differentiation, and in multiple aspects of stress response in the nervous system. The opposite roles of closely related sphingolipid species in cell survival/death signaling is reflected in the concept of tightly controlled sphingolipid rheostat. Aging has a complex influence on sphingolipid metabolism, disturbing signaling pathways and the properties of lipid membranes. A metabolic signature of stress resistance-associated sphingolipids correlates with longevity in humans. Moreover, accumulating evidence suggests extensive links between sphingolipid signaling and the insulin-like growth factor I (IGF-I)-Akt-mTOR pathway (IIS), which is involved in the modulation of aging process and longevity. IIS integrates a wide array of metabolic signals, cross-talks with p53, nuclear factor κB (NF-κB), or reactive oxygen species (ROS) and influences gene expression to shape the cellular metabolic profile and stress resistance. The multiple connections between sphingolipids and IIS signaling suggest possible engagement of these compounds in the aging process itself, which creates a vulnerable background for the majority of neurodegenerative disorders.

Keywords: Aging; Ceramide; Insulin-like growth factor; Mitochondria; Neurodegeneration; Sphingosine-1-phosphate.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Sphingolipid metabolism and the three pathways of ceramide biosynthesis. The scheme shows only selected reactions and enzymes, plus their feedback regulation by S1P and C1P. C1P, ceramide-1-phosphate; C1PP, C1P phosphatase; CerK, ceramide kinase; CerS, (dihydro)ceramide synthase; S1P, sphingosine-1-phosphate; SGMS, sphingomyelin synthase; SGPP, S1P phosphatase; SMase, sphingomyelinase; SPT, serine palmitoyltrasnferase
Fig. 2
Fig. 2
Modulation of the PI3K-Akt-mTOR signaling by bioactive sphingolipids. Bi-directional interactions with cellular stress, aging, and neurodegeneration. Selected enzymes of sphingolipid metabolism with known significance for the modification of the aging process are shown. Akt, protein kinase B; C1P, ceramide-1-phosphate; Cer, ceramide; CerK, ceramide kinase; CerS (LASS), ceramide synthase; HIF-1α, hypoxia-inducible factor-1α; IGF-IR, insulin-like growth factor receptor; IKK, inhibitor of NF-κB kinase; mTORC1, mammalian (or: mechanistic) target of rapamycin complex 1; NF-κB, nuclear factor κB; PAM, protein associated with Myc; PI3K, class I phosphoinositide 3-kinase; PLD, phospholipase D; Rheb, Ras homolog enriched in the brain; RNS, reactive nitrogen species; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; S1PR, cell surface G protein-binding S1P receptors; Sph, sphingosine; SphK, sphingosine kinase(s); TSC, tuberous sclerosis protein. formula image symbols denote varied/ambiguous influence (e.g., depending on the cell model used, the presence of RNS has been found to either activate or inhibit IKKβ). The scheme skips additional interactions, such as the links between ceramide itself and stress, the inhibitory phosphorylation of TSC1 by IKKβ, or feedback influences of mTOR on PI3K-Akt. Sphingolipids can modulate mTOR in multiple ways, potentially allowing cell type/subcellular compartment-specific functioning of the S1P-mTOR branch. mTORC1 activation occurs on the surface of various organellar membranes, and details of the pathway may be different depending on the cell region. According to [3, 52], modified
Fig. 3
Fig. 3
Selected mediators of mTORC1 signaling in the modulation of cellular metabolism and organism lifespan. Fragmented evidence shows that sphingolipids can lead to opposite effects on mTORC1 activity, depending on the mediators engaged, or experimental model used (see text). The mTORC1 complex influences protein quality assurance mechanisms through heat shock transcription factor 1 (HSF1) and the Unc-51-like kinase (ULK1) [190]. mTORC1 stimulates transcription (via ribosomal S6 kinase (S6K)), and translation (through blocking of 4E binding protein 4E-BP1, which itself is an inhibitor of eukaryotic translation initiation factor 4E-eIF4E). 4E-BP1 can react positively to the presence of ceramide, although the mechanism has not been fully elucidated. Sterol regulatory element-binding protein (SREBP-1c) mediates the effect of mTOR on lipid biosynthesis [191]. The extremely pleiotropic functions of NF-κB include regulation of the glycolysis-controlling hypoxia inducible factor 1α (HIF1α), sirtuin (SIRT1), and forkhead box O1 transcription factors (FOXOs, which can send feedback signal to S1P receptors), and antioxidative enzymes glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD). According to [192], modified
Fig. 4
Fig. 4
Bioactive sphingolipids and their roles in mitochondrial fusion, fission, autophagy/mitophagy, and apoptotic signaling. Ceramide is capable of activating mitophagy (via microtubule-associated protein 1A/1B-light chain 3 proteins (LC3)) and mitochondrial fission (through Bcl-2-related ovarian killer protein (BOK)), while inhibiting fusion (through mitofusin 1 and the optic atrophy protein (OPA1); see text for details. S1P generally activates autophagy, although the significance of this fact for mitochondrial turnover is not yet known. However, S1P augments mitochondrial assembly via protein kinase A (PKA), peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α), and prohibitin 2. S1P and ceramide regulate the anti-apoptotic Bcl-2 and the Bcl-2 family protein: BclxL, and pro-apoptotic Bax, Bad, or Bim. In turn, some of the proteins influence the enzymes of sphingolipid metabolism, ensuring negative or positive feedback regulation
Fig. 5
Fig. 5
The significance of bioactive sphingolipids in neurodegeneration. The ‘sphingolipid rheostat’ model assumes antagonistic roles of ceramide and S1P in the regulation of cellular survival and death. Although exceptions have been identified, the tendency towards accumulation of ceramide and reduced levels of S1P still should generate strong neurodegenerative impulse. Potential downstream mechanisms include not only inhibition of survival signaling mostly mediated by the PI3K-Akt pathway, but also modulation of AβPP metabolism, and alteration of S1PR-dependent immune response—the latter capable of exerting either beneficial (Aβ clearance) or detrimental outcome (damage to neurons). formula image symbol denotes the ambiguous role of immune activation in neurodegenerative disorders (clearance of extracellular aggregates of misfolded proteins and debris from dying cells vs. creation of neurotoxic environment that accelerates the loss of neuronal connectivity and ultimately death of further neurons). S1P is known to modulate the immune response, but the possible outcome of the resulting reaction in the diseased brain is highly unclear

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