Sphingomyelinases and Liver Diseases

Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. Ceramide is a heterogeneous lipid entity determined by the length of the fatty acyl chain linked to its carbon backbone sphingosine, which can be generated either by de novo synthesis from serine and palmitoyl-CoA in the endoplasmic reticulum or via sphingomyelin (SM) hydrolysis by sphingomyelinases (SMases). Unlike de novo synthesis, SMase-induced SM hydrolysis represents a rapid and transient mechanism of ceramide generation in specific intracellular sites that accounts for the diverse biological effects of ceramide. Several SMases have been described at the molecular level, which exhibit different pH requirements for activity: neutral, acid or alkaline. Among the SMases, the neutral (NSMase) and acid (ASMase) are the best characterized for their contribution to signaling pathways and role in diverse pathologies, including liver diseases. As part of a Special Issue (Phospholipases: From Structure to Biological Function), the present invited review summarizes the physiological functions of NSMase and ASMase and their role in chronic and metabolic liver diseases, of which the most relevant is nonalcoholic steatohepatitis and its progression to hepatocellular carcinoma, due to the association with the obesity and type 2 diabetes epidemic. A better understanding of the regulation and role of SMases in liver pathology may offer the opportunity for novel treatments of liver diseases.

Download Full-text

Phospholipid Remodeling in Physiology and Disease

Annual Review of Physiology ◽

10.1146/annurev-physiol-020518-114444 ◽

2019 ◽

Vol 81 (1) ◽

pp. 165-188 ◽

Cited By ~ 36

Author(s):

Bo Wang ◽

Peter Tontonoz

Keyword(s):

Viral Infections ◽

De Novo ◽

Acyl Chain ◽

Phospholipid Composition ◽

Fatty Acyl ◽

De Novo Lipogenesis ◽

Lipid Absorption ◽

Fatty Acyl Chain ◽

Nonalcoholic Fatty Liver ◽

Acyl Chains

Phospholipids are major constituents of biological membranes. The fatty acyl chain composition of phospholipids determines the biophysical properties of membranes and thereby affects their impact on biological processes. The composition of fatty acyl chains is also actively regulated through a deacylation and reacylation pathway called Lands’ cycle. Recent studies of mouse genetic models have demonstrated that lysophosphatidylcholine acyltransferases (LPCATs), which catalyze the incorporation of fatty acyl chains into the sn-2 site of phosphatidylcholine, play important roles in pathophysiology. Two LPCAT family members, LPCAT1 and LPCAT3, have been particularly well studied. LPCAT1 is crucial for proper lung function due to its role in pulmonary surfactant biosynthesis. LPCAT3 maintains systemic lipid homeostasis by regulating lipid absorption in intestine, lipoprotein secretion, and de novo lipogenesis in liver. Mounting evidence also suggests that changes in LPCAT activity may be potentially involved in pathological conditions, including nonalcoholic fatty liver disease, atherosclerosis, viral infections, and cancer. Pharmacological manipulation of LPCAT activity and membrane phospholipid composition may provide new therapeutic options for these conditions.

Download Full-text

Regulating effect of β-ketoacyl synthase domain of fatty acid synthase on fatty acyl chain length in de novo fatty acid synthesis

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2015.12.002 ◽

2016 ◽

Vol 1861 (3) ◽

pp. 149-155 ◽

Cited By ~ 5

Author(s):

Wei Cui ◽

Yan Liang ◽

Weixi Tian ◽

Mingjuan Ji ◽

Xiaofeng Ma

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthesis ◽

Fatty Acid Synthase ◽

De Novo ◽

Acyl Chain ◽

Acid Synthesis ◽

Fatty Acyl ◽

Fatty Acyl Chain ◽

Acyl Chain Length ◽

Ketoacyl Synthase

Download Full-text

Fatty acyl chain structure, orientational order, and the lipid phase transition in Acholeplasma laidlawii B membranes. A review of recent 19F nuclear magnetic resonance studies

Canadian Journal of Biochemistry and Cell Biology ◽

10.1139/o84-147 ◽

1984 ◽

Vol 62 (11) ◽

pp. 1134-1150 ◽

Cited By ~ 16

Author(s):

P. M. Macdonald ◽

B. D. Sykes ◽

R. N. McElhaney

Keyword(s):

Phase Transition ◽

Fatty Acids ◽

Nuclear Magnetic Resonance ◽

Acyl Chain ◽

Orientational Order ◽

Membrane Lipid ◽

Fatty Acyl ◽

Fatty Acyl Chain ◽

Lipid Phase ◽

Lipid Phase Transition

The orientational order parameters of monofluoropalmitic acids biosynthetically incorporated into membranes of Acholeplasma laidlawii B in the presence of a large excess of a variety of structurally diverse fatty acids have been determined via 19F nuclear magnetic resonance (19F NMR) spectroscopy. It is demonstrated that these monofluoropalmitic acids are relatively nonperturbing membrane probes based upon physical (differential scanning calorimetry), biochemical (membrane lipid analysis), and biological (growth studies) criteria. 19F NMR is shown to convey the same qualitative and quantitative picture of membrane lipid order provided by 2H-NMR techniques and to be sensitive to the structural characteristics of the membrane fatty acyl chains, as well as to the lipid phase transition. Representatives of each naturally occurring class of fatty acyl chain structures, including straight-chain saturated, methyl-branched, monounsaturated, and alicyclic-ring-substituted fatty acids, were studied and the 19F-NMR order parameters were correlated with the lipid phase transitions (determined calorimetrically). The lipid phase transition was the prime determinant of overall orientational order regardless of fatty acid structure. Effects upon orientational order attributable to specific structural substituents were discernible, but were secondary to the effects of the lipid phase transition. In the gel state, relative overall order was directly proportional to the temperature of the particular lipid phase transition. Not only the overall order, but also the order profile across the membrane was sensitive to the presence of particular structural substituents. In particular, in the gel state specific fatty acyl structures demonstrated a characteristic disordering effect in the membrane order profile. These various observations can be merged to provide a unified picture of the manner in which fatty acyl chain chemistry modulates the physical state of membrane lipids.

Download Full-text

The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy

Cancers ◽

10.3390/cancers13102475 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2475

Author(s):

Megan Sheridan ◽

Besim Ogretmen

Keyword(s):

Cancer Therapy ◽

Acyl Chain ◽

Fatty Acyl ◽

Fatty Acyl Chain ◽

Cancer Cell Proliferation ◽

Bioactive Lipids ◽

Cellular Functions ◽

Proliferation Response ◽

Ceramide Synthases

Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.

Download Full-text

Effect of fatty acyl chain length and structure on the lamellar gel to liquid-crystalline and lamellar to reversed hexagonal phase transitions of aqueous phosphatidylethanolamine dispersions

Biochemistry ◽

10.1021/bi00428a020 ◽

1989 ◽

Vol 28 (2) ◽

pp. 541-548 ◽

Cited By ~ 87

Author(s):

Ruthven N. A. H. Lewis ◽

David A. Mannock ◽

Ronald N. McElhaney ◽

David C. Turner ◽

Sol M. Gruner

Keyword(s):

Phase Transitions ◽

Chain Length ◽

Liquid Crystalline ◽

Hexagonal Phase ◽

Acyl Chain ◽

Fatty Acyl ◽

Fatty Acyl Chain ◽

Acyl Chain Length

Download Full-text

Effect of Acylglycerol Composition and Fatty Acyl Chain Length on Lipid Digestion in pH-Stat Digestion Model and SimulatedIn VitroDigestion Model

Journal of Food Science ◽

10.1111/1750-3841.13196 ◽

2015 ◽

Vol 81 (2) ◽

pp. C317-C323

Author(s):

Jin F. Qi ◽

Cai H. Jia ◽

Jung A. Shin ◽

Jeong M. Woo ◽

Xiang Y. Wang ◽

...

Keyword(s):

Chain Length ◽

Acyl Chain ◽

Fatty Acyl ◽

Fatty Acyl Chain ◽

Lipid Digestion ◽

Acyl Chain Length ◽

Ph Stat

Download Full-text

Acyltransferase-mediated selection of the length of the fatty acyl chain and of the acylation site governs activation of bacterial RTX toxins

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014122 ◽

2020 ◽

Vol 295 (28) ◽

pp. 9268-9280 ◽

Cited By ~ 3

Author(s):

Adriana Osickova ◽

Humaira Khaliq ◽

Jiri Masin ◽

David Jurnecka ◽

Anna Sukova ◽

...

Keyword(s):

Acyl Chain ◽

Fatty Acyl ◽

Biologically Active ◽

Fatty Acyl Chain ◽

Acyl Carrier Proteins ◽

E Coli ◽

Rtx Toxins ◽

Wide Range ◽

Lysine Residues ◽

Acyl Chains

In a wide range of organisms, from bacteria to humans, numerous proteins have to be posttranslationally acylated to become biologically active. Bacterial repeats in toxin (RTX) cytolysins form a prominent group of proteins that are synthesized as inactive protoxins and undergo posttranslational acylation on ε-amino groups of two internal conserved lysine residues by co-expressed toxin-activating acyltransferases. Here, we investigated how the chemical nature, position, and number of bound acyl chains govern the activities of Bordetella pertussis adenylate cyclase toxin (CyaA), Escherichia coli α-hemolysin (HlyA), and Kingella kingae cytotoxin (RtxA). We found that the three protoxins are acylated in the same E. coli cell background by each of the CyaC, HlyC, and RtxC acyltransferases. We also noted that the acyltransferase selects from the bacterial pool of acyl–acyl carrier proteins (ACPs) an acyl chain of a specific length for covalent linkage to the protoxin. The acyltransferase also selects whether both or only one of two conserved lysine residues of the protoxin will be posttranslationally acylated. Functional assays revealed that RtxA has to be modified by 14-carbon fatty acyl chains to be biologically active, that HlyA remains active also when modified by 16-carbon acyl chains, and that CyaA is activated exclusively by 16-carbon acyl chains. These results suggest that the RTX toxin molecules are structurally adapted to the length of the acyl chains used for modification of their acylated lysine residue in the second, more conserved acylation site.

Download Full-text

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1522071113 ◽

2016 ◽

Vol 113 (21) ◽

pp. 5928-5933 ◽

Cited By ~ 24

Author(s):

Stefka D. Spassieva ◽

Xiaojie Ji ◽

Ye Liu ◽

Kenneth Gable ◽

Jacek Bielawski ◽

...

Keyword(s):

Acyl Chain ◽

Strong Association ◽

Ectopic Expression ◽

Fatty Acyl ◽

Chemical Diversity ◽

Fatty Acyl Chain ◽

Length Variation ◽

Ceramide Synthase ◽

Hydrophobic Moiety

Sphingolipids exhibit extreme functional and chemical diversity that is in part determined by their hydrophobic moiety, ceramide. In mammals, the fatty acyl chain length variation of ceramides is determined by six (dihydro)ceramide synthase (CerS) isoforms. Previously, we and others showed that mutations in the major neuron-specific CerS1, which synthesizes 18-carbon fatty acyl (C18) ceramide, cause elevation of long-chain base (LCB) substrates and decrease in C18 ceramide and derivatives in the brain, leading to neurodegeneration in mice and myoclonus epilepsy with dementia in humans. Whether LCB elevation or C18 ceramide reduction leads to neurodegeneration is unclear. Here, we ectopically expressed CerS2, a nonneuronal CerS producing C22–C24 ceramides, in neurons of Cers1-deficient mice. Surprisingly, the Cers1 mutant pathology was almost completely suppressed. Because CerS2 cannot replenish C18 ceramide, the rescue is likely a result of LCB reduction. Consistent with this hypothesis, we found that only LCBs, the substrates common for all of the CerS isoforms, but not ceramides and complex sphingolipids, were restored to the wild-type levels in the Cers2-rescued Cers1 mutant mouse brains. Furthermore, LCBs induced neurite fragmentation in cultured neurons at concentrations corresponding to the elevated levels in the CerS1-deficient brain. The strong association of LCB levels with neuronal survival both in vivo and in vitro suggests high-level accumulation of LCBs is a possible underlying cause of the CerS1 deficiency-induced neuronal death.

Download Full-text