Ceramide

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Ceramide. R represents the alkyl portion of a fatty acid.
General structures of sphingolipids

Ceramides are a family of

differentiation, proliferation, and programmed cell death (PCD) of cells
.

The word ceramide comes from the Latin cera (wax) and amide. Ceramide is a component of vernix caseosa, the waxy or cheese-like white substance found coating the skin of newborn human infants.

Pathways for ceramide synthesis

There are three major pathways of ceramide generation. First, the sphingomyelinase pathway uses an enzyme to break down sphingomyelin in the cell membrane and release ceramide. Second, the de novo pathway creates ceramide from less complex molecules. Third, in the "salvage" pathway, sphingolipids that are broken down into sphingosine are reused by reacylation to form ceramide.

Sphingomyelin hydrolysis

plasma membrane of cells, the implications of this method of generating ceramide is that the cellular membrane is the target of extracellular signals leading to programmed cell death. There has been research suggesting that when ionizing radiation causes apoptosis in some cells, the radiation leads to the activation of sphingomyelinase in the cell membrane and ultimately, to ceramide generation.[2]

De novo

De novo synthesis of ceramide begins with the condensation of

Salvage pathway

Constitutive degradation of sphingolipids and glycosphingolipids takes place in the acidic subcellular compartments, the late endosomes and the

ceramide synthase family members probably trap free sphingosine released from the lysosome at the surface of the endoplasmic reticulum or in endoplasmic reticulum-associated membranes. The salvage pathway has been estimated to contribute from 50% to 90% of sphingolipid biosynthesis.[4]

Physiological roles

Pathology

As a bioactive lipid, ceramide has been implicated in a variety of physiological functions including

neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation.[5][6]

Several distinct ceramides potently predict

non-alcoholic fatty liver disease (NAFLD) is associated with elevated ceramide in hepatocytes.[8] Dietary intake of saturated fat has been shown to increase serum ceramide and increase insulin resistance.[7] Although initial studies showed increased insulin resistance in muscle, subsequent studies also showed increased insulin resistance in liver and adipose tissue.[8] Interventions that limit ceramide synthesis or increase ceramide degradation lead to improved health (reduced insulin resistance and reduced fatty liver disease, for example).[7]

Ceramides induce skeletal muscle insulin resistance when synthesized as a result of saturated fat activation of

TLR4 receptors.[9] Unsaturated fat does not have this effect.[9] Ceramides induce insulin resistance in many tissues by inhibition of Akt/PKB signaling.[10] Aggregation of LDL cholesterol by ceramide causes LDL retention in arterial walls, leading to atherosclerosis.[11] Ceramides cause endothelial dysfunction by activating protein phosphatase 2 (PP2A).[12] In mitochondria, ceramide suppresses the electron transport chain and induces production of reactive oxygen species.[13]

Apoptosis

One of the most studied roles of ceramide pertains to its function as a proapoptotic molecule.

mitochondria in inducing apoptosis. However, owing to the conflicting and variable nature of studies into the role of ceramide in apoptosis, the mechanism by which this lipid regulates apoptosis remains elusive.[17]

Skin

The

epidermis.[18][19][20] It is composed of terminally differentiated and enucleated corneocytes that reside within a lipid matrix, like "bricks and mortar." Together with cholesterol and free fatty acids, ceramides form the lipid mortar, a water-impermeable barrier that prevents evaporative water loss. As a general rule of thumb, the epidermal lipid matrix is composed of an equimolar mixture of ceramides (~50% by weight), cholesterol (~ 25% by weight), and free fatty acids (~15% by weight), with smaller quantities of other lipids also being present.[21][22] The lipid barrier also protects against the entry of microorganisms.[20]

Epidermal ceramides have a diversity of structures and can be broadly classified as AS and NS ceramides; ADS and NDS dihydroceramides; AH, EOH, and NH 6-hydroxyceramides; AP and NP phytoceramides; and EOH and EOS acylceramides, see figure.

Epidermal Ceramides. (Merleev et. al., JCI Insight 2022, Supplemental Data p.14- Supplemental Fig. 1)

[18] The diversity of ceramide structures undoubtedly plays an important role in the unique attributes of the stratum corneum across different body sites. For example, the stratum corneum of the face is thin and flexible to accommodate different facial expressions. In contrast, the stratum corneum covering the heel of the foot is thick and rigid to protect against trauma. Matching these structural changes, there are body-site specific alterations in the epidermal lipidome, including changes in the relative abundance of the different epidermal ceramide structures.[18]

Similar to body site-specific alterations in ceramide abundance, there are also well-characterized changes in epidermal ceramide expression in patients with inflammatory skin diseases. In the hyperplastic disorder psoriasis, investigators have reported an increase in AS and NS ceramides and a decrease in EOS, AP, and NP ceramides, which may contribute to a defect in the skin's water impermeability barrier.[23][24][22] Studying ceramide expression in atopic dermatitis and psoriasis patients, other investigators have reported that rather than focusing on ceramide classes, ceramide sphingoid base length and fatty acid chain length have the strongest influence on the likelihood of a particular ceramide structure being upregulated or downregulated in inflamed skin.[18]

Hormonal

Inhibition of ceramide synthesis with

SOCS-3 expression.[25] An elevated level of ceramide can cause insulin resistance by inhibiting the ability of insulin to activate the insulin signal transduction pathway and/or via the activation of JNK.[26]

Substances known to induce ceramide generation

Mechanism by which ceramide signaling occurs

Currently, the means by which ceramide acts as a signaling molecule are not clear.

One hypothesis is that ceramide generated in the

lipid rafts
, allowing them to serve as platforms for signalling molecules. Moreover, as rafts on one leaflet of the membrane can induce localized changes in the other leaflet of the bilayer, they can potentially serve as the link between signals from outside the cell to signals to be generated within the cell.

Ceramide has also been shown to form organized large channels traversing the mitochondrial outer membrane. This leads to the egress of proteins from the intermembrane space.[32][33][34]

Related diseases

In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3, a massive altered composition of complex lipids occurs as a result of impaired mitochondrial fatty acid synthesis (mtFAS).[35][36] For example, while the concentration of sphingomyelin is noticeably increased, the concentration of ceramides is proportionally decreased.[35]

Uses

Ceramides may be found as ingredients of some topical skin medications used to complement treatment for skin conditions such as

eczema.[37] They are also used in cosmetic products such as some soaps, shampoos, skin creams, and sunscreens.[38] Additionally, ceramides are being explored as a potential therapeutic in treating cancer.[39]

Ceramide in bacteria

Ceramide is rarely found in bacteria.[40] Bacteria of family Sphingomonadaceae, however, contain it.

Ceramide phosphoethanolamine

Ceramide phosphoethanolamine (CPE) is a

phosphoethanolamine head group. CPE is the major sphingolipid class in some invertebrates such as members of Drosophila
. In contrast, mammalian cells contain only small amounts of CPE.

References

External links