ReviewBiochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain
Section snippets
Abreviations
C1P Ceramide-1-Phosphate Cerk Ceramide kinase Cers Ceramide synthases Cert Ceramide transfer protein CF Cystic Fibrosis CFTR Cystic Fibrosis Transmembrane Regulator Cptp C1P transport protein Degs Sphingolipid delta(4)-desaturases DRMs Detergent Resistant Membranes ELISA Enzyme-Linked Immunosorbent Assay ER Endoplasmic Reticulum FABP Fatty Acid Binding Protein Fapp2 Four-phosphate adaptor protein 2 FEV1 Forced expiratory volume in one second fln flincher Gba Glucosylceramidase GM1, GD1a, GD1b, and GT1b
Cystic fibrosis
Cystic fibrosis is the most common genetic disease in Caucasians with an incidence of 1 in 3000 births in Western countries [1]. Even though it was first described back in 1936 and 1938 by Fanconi and Andersen respectively [2,3], it was not until 1989 that an underlying genetic defect in cystic fibrosis transmembrane regulator (CFTR) was discovered by Francis Collins and Lap-Chee Tsui [4,5].This discovery laid ground for all future investigations of cystic fibrosis. CFTR gene, located at the
Metabolism of sphingolipids
In the late 19th century, JWL Tudichum was the first to recognize the enigmatic nature of a brain lipid that he isolated and named it “sphingosine” after the Sphinx, a creature from Greek mythology that devoured all the passengers who could not answer the riddle it was posing to them [24]. Indeed, sphingosine, an amino-alcohol of 18 carbons, and its relatives known as sphingolipids continue to present an enigma to all of us studying them to this day. Biochemical steps in the synthesis of
Metabolic actions of ceramides
Ceramides have long been known to be ubiquitous building blocks of eukaryotic cell membranes and signaling molecules produced mostly upon various exogenous stimuli like inflammation or stress. Therefore, the roles of ceramides in the cell can be view as structural components of the cellular membranes and as metabolic/bioactive, as the signaling molecules produced upon various stimuli.
Despite their involvement in numerous biological processes, remarkably little mechanistic insight has been
Ceramides as structural elements of biological membranes
The mechanistic basis and the biochemical pathways behind the phenotypes seen in the ceramide synthases knockout mice have not been fully explored yet. Part of the answer to these questions seems to lie in the structural role of ceramides as the fundamental building blocks of all eukaryotic cell membranes.
Ceramides form the intramembraneous backbone of all sphingolipids, including sphingomyelins. Sphingomyelins consist of phosphocholine or phosphoethanolamine bound to a ceramide backbone
Ceramides in CF
The first connection between ceramides and pulmonary infection with P. aeruginosa, the most common pathogen in the lungs in CF patients, was made by the group of Richard Blumberg. In their study, Neiuwenhuis and colleagues treated imunodeficient CD1d −/− mice with (2S, 3S, 4R)-1-O-(α-D-Galactosyl)-N-hexacosanoyl-2-amino-1,3,4-octadecanetriol (shortly named KRN7000), a compound similar to the naturally occurring α-galactosylceramide which is a ligand that activates NK cells and macrophages when
Ceramides and CFTR
CFTR is a large, intrinsically disordered protein [99] that is primarily localized at the apical domain of epithelial cells [100]. Each CFTR molecule contains two membrane –spanning domains (MSD1 and MSD2), two nucleotide binding domains that participate in ATP binding and hydrolysis (NBD1 and NBD2), and a regulatory domain (R) whose phosphorylation by protein kinase A (PKA) regulates opening of the channel [101]. The folding of the wild-type CFTR protein is slow and relatively inefficient due
Technical challenges in ceramide quantification
Much of the confusion in the current literature about the role of ceramides in health and disease arises from the flaws in the methods used for their quantification. Traditionally, ceramides have been quantified in biological samples using antibodies and mass spectroscopy. The results obtained from these studies sometimes led to fundamentally different conclusions [93,95].
In our previous work, we utilized 15B4 anti-ceramide monoclonal antibody from Sigma to quantify the total ceramide levels in
Conclusion
The sphingolipids family have been widely investigated for their role as structural and functional physiologically active molecules, yet their role still remains a riddle that fully justifies their name to this day. Ceramides, the basic building blocks of all sphingolipids, are important molecules in the physiology of lungs, with implications for diseases like cystic fibrosis. Intricacies in their structures, especially the length of their side acyl chain, seem to play previously unappreciated
Supplement
The mixture of 25 μl of brain lipid extract in chloroform (Avanti 131101C), subjected to thin-layer chromatography on the silica plate, and transferred to nytran membrane by diffusion. After separation on silica gel, standards were visualized after 30 min incubation in iodine vapor.
The Fig. 8B illustrates comparison of the binding of polyclonal and monoclonal antibodies against ceramides mixture commercially available from Sigma and Glycobiotech to various species of ceramides. Commercially
Acknowledgements
We want to acknowledge financial support from Canadian Institutes of Health Research (POP90155, account 6071), Canadian Cystic Fibrosis Foundation via McGill University (account 3645), Department for Administration and Development project, Ministry of Education, Youth and Sport, Czech Republic, Molecular and Cellular Clinical Approach to Healthy Ageing (ENOCH project) via IMTM (#869/V19).
References (125)
- et al.
The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells
J Biol Chem
(1993) - et al.
Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis
Cell
(1990) - et al.
Early inflammation in the airways of a cystic fibrosis foetus
J Cyst Fibros
(2007) - et al.
Eleven residues determine the acyl chain specificity of ceramide synthases
J Biol Chem
(2018) - et al.
Chain length-specific properties of ceramides
Prog Lipid Res
(2012) - et al.
Many ceramides
J Biol Chem
(2011) - et al.
Lipid phosphate phosphatases and their roles in mammalian physiology and pathology
J Lipid Res
(2015) - et al.
CERT mediates intermembrane transfer of various molecular species of ceramides
J Biol Chem
(2005) Serine/threonine phosphatases: mechanism through structure
Cell
(2009)- et al.
Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex
J Biol Chem
(2000)
The carboxyl-terminal domain of atypical protein kinase Czeta binds to ceramide and regulates junction formation in epithelial cells
J Biol Chem
Protein phosphatase 1alpha mediates ceramide-induced ERM protein dephosphorylation: a novel mechanism independent of phosphatidylinositol 4, 5-biphosphate (PIP2) and myosin/ERM phosphatase
J Biol Chem
Apoptosis and activation of the sphingomyelin-ceramide pathway induced by oxidized low density lipoproteins are not causally related in ECV-304 endothelial cells
J Biol Chem
Mass spectrometric identification of increased C16 ceramide levels during apoptosis
J Biol Chem
Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha
J Biol Chem
Induction of apoptosis through B-cell receptor cross-linking occurs via de novo generated C16-ceramide and involves mitochondria
J Biol Chem
Activation of ceramide synthase 6 by celecoxib leads to a selective induction of C16:0-ceramide
Biochem Pharmacol
Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins
J Biol Chem
Ceramide channels: destabilization by Bcl-xL and role in apoptosis
Biochim Biophys Acta
Very long chain ceramides interfere with C16-ceramide-induced channel formation: a plausible mechanism for regulating the initiation of intrinsic apoptosis
Biochim Biophys Acta
Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth
Int J Biochem Cell Biol
A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells
Biochim Biophys Acta
Modulation of ceramide synthase activity via dimerization
J Biol Chem
Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes
J Biol Chem
Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length
J Invest Dermatol
Ceramide synthase 5 is essential to maintain C16:0-ceramide pools and contributes to the development of diet-induced obesity
J Biol Chem
Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities
J Biol Chem
Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance
Cell Metab
Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas
J Biol Chem
A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways
J Biol Chem
A critical role for ceramide synthase 2 in liver homeostasis: II. insights into molecular changes leading to hepatopathy
J Biol Chem
TRAM, LAG1 and CLN8: members of a novel family of lipid-sensing domains?
Trends Biochem Sci
A new functional motif in Hox domain-containing ceramide synthases: identification of a novel region flanking the Hox and TLC domains essential for activity
J Biol Chem
Ceramide synthase schlank is a transcriptional regulator adapting gene expression to energy requirements
Cell Rep
The preferential interaction of cholesterol with different classes of phospholipids
Biochim Biophys Acta
Lipid rafts as major platforms for signaling regulation in cancer
Adv Biol Regul
Permeability and microstructure of model stratum corneum lipid membranes containing ceramides with long (C16) and very long (C24) acyl chains
Biophys Chem
Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes
J Lipid Res
Influence of chain length and unsaturation on sphingomyelin bilayers
Biophys J
Effect of ceramide tail length on the structure of model stratum corneum lipid bilayers
Biophys J
Ceramide mediates lung fibrosis in cystic fibrosis
Biochem Biophys Res Commun
A simple method for the isolation and purification of total lipides from animal tissues
J Biol Chem
Cystic fibrosis genetics: from molecular understanding to clinical application
Nat Rev Genet
Das Coelikisyndrom bie angeboren zystischer Pancreafibromatose und Bronchiektasien
Wien Med Wochenschr
Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study
Am J Dis Child
Identification of the cystic fibrosis gene: genetic analysis
Science
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA
Science
Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis
N Engl J Med
VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles
N Engl J Med
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
Proc Natl Acad Sci U S A
Cited by (26)
Emerging roles and therapeutic potentials of sphingolipids in pathophysiology: emphasis on fatty acyl heterogeneity
2024, Journal of Genetics and GenomicsDecreased plasma levels of sphingolipids and total cholesterol in adult cystic fibrosis patients
2023, Prostaglandins Leukotrienes and Essential Fatty AcidsAzadirachtin exposure inhibit ovary development of Spodoptera litura (Lepidoptera: Noctuidae) by altering lipids metabolism event and inhibiting insulin signaling pathways
2023, Ecotoxicology and Environmental SafetyThe role of the ‘sphingoid motif’ in shaping the molecular interactions of sphingolipids in biomembranes
2021, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :The unique properties of the first five carbons of the sphingoid long chain base (LCB) are derived from the two carbon atoms donated from the amino acid and the three donated from the acyl CoA; we hereby propose that these five defining carbon atoms be termed the ‘sphingoid motif’. The sphingoid motif displays considerable structural variability (see Section 2 below), such as the degree of saturation and the nature of substituents [7,8], and is responsible for the majority of the interactions of SLs with other membrane lipids and membrane proteins; however, the two hydrophobic chains of SLs also play critical roles in the biophysical and biological functions of these lipids [9], as attested by the range of neurological and metabolic disorders associated with changes in the length and degree of unsaturation of these two acyl chains [10–12]. The structural features that we will discuss below relate mainly to the sphingoid motif, which gives SLs the unique ability to donate hydrogen bonds via their hydroxyl and amide hydrogen atoms (Fig. 1), which is in contrast to the extent of hydrogen-bonding associated with glycerophospholipids [13].