Ceramide

2022-08-11: reference:

Ceramide #

• From Molecules to the Clinic: Linking Schizophrenia and Metabolic Syndrome through Sphingolipids Metabolism (2016)

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    • is this comprehensive, or what? Not sure
    • (They skipped 3-keto-dihydrosphingosine -> Sphinganine)
    • There are 6 Ceramide Synthase subtypes each with fatty acid specificity:
      • CerS1: Specifically Stearic Acid. Basically only in brain and skeletal muscle.
      • CerS2: C20-26. Highest expression of all CerS in oligodendrocytes/Schwann cells.
    • Indeed, this de novo synthesis of ceramide is the rate-limiting step of the synthesis of all the complex sphingolipids, sphingomyelin, and so on.

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  • In schizophrenia’s structural sphingolipid abnormality, myelin-associated glycoprotein and myelin/oligodendrocyte glycoprotein are segregated from the lipid raft.

• Similarly, The Role of Ceramides in Insulin Resistance (2019)

• Ceramide function in the brain: when a slight tilt is enough

  • De novo synthesis of ceramides takes place on the cytoplasmic face of the Smooth Endoplasmic Reticulum and in mitochondria.
    • Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver
  • all these things stimulate. The study describes most of these things as ‘inducers of cell death’. Ceramide production results in cell deaht.

• Ceramide channels and mitochondrial outer membrane permeability

  • They permeabilize the Outer Mitochondrial Membrane
  • The dogma in early mitochondrial research was that channels had to be small and highly selective.
  • It is uncertain in which direction the influence is, but it synergizes with BAX in permeabilizing the MOM.

• Bioactive sphingolipids in the modulation of the inflammatory response

  • SphK1 and CERK1 are probably effectors of cytokine-mediated Prostaglandin generation in inflammatory conditions.
    • It was shown that S1P pathway but not C1P pathway mediated IL-1β-mediated COX-2 induction.
    • Ceramide-1-phosphate activates cPLA2.
    • PLA2/COX-2 colocalized with the golgi and perinuclear regions in response to S1P/C1P treatment.
    • LPS treatment produces rapid rise of ceramide in Macrophages. LPS as well as ceramide analogues induce TNF-α secretion. However, the fact that LPS but not ceramide analogues stimulated interferon activity suggested that ceramide induced only a subset of LPS-induced genes.

• Ceramide-1-phosphate (via ceramide kinase). This facilitates localization of p-Phospholipase A2 to the trans-Golgi

  • Indeed it locazlies to the COX-2-localization site on the Outer Mitochondrial Membrane
  • Autophagy in the light of sphingolipid metabolism
    • Promotes Ca2+-dependent Liposomeal fusion, enhancing vesicle fusion.
    • C1P levels increase during phagocytosis, indicating that C1P may promote fusion between phagosomes and lysosomes

Neurodegenerative Disease #

• Triangulated mal-signaling in Alzheimer’s disease: roles of neurotoxic ceramides, ER stress, and insulin resistance reviewed.
  • Ceramide accumulation appears to be bidirectional with oxidative/ER stress and neuroinflammation.
• Amyloid-β peptide induces oligodendrocyte death by activating the neutral sphingomyelinase–ceramide pathway
  • Activates neutral sphingomyelinase - but not Acid Sphingomyelinase…
  • Blocking ceramide degradation with Oleoylethanolamine exacerbated Aβ cytotoxicity.
  • Addition of sphingomyelinase (from bacteria) induced Oligodendrocyte death.
• Astrocytic ceramide as possible indicator of neuroinflammation (In frontotemporal lobar dmentia Pick’s disease)
• Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer’s Disease
• I swear they can be as short as 14 carbons or as long as 26.
• Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response

Phytoceramide #

• Phytoceramide has an extra hydroxyl group.
• Administration of Phytoceramide Enhances Memory and Upregulates the Expression of pCREB and BDNF in Hippocampus of Mice
  • Elevated p-CREB and BDNF in mice assessed with passive avoidance and Y-maze task. 50mg/kg was the only significant one.