Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target?
Abstract
:1. Introduction
2. Sphingolipids: Fundamentals of Biology and Metabolism
2.1. Sphingolipid Biosynthesis, Metabolism, and Catabolism
2.1.1. Sphingoid Bases
2.1.2. Ceramides
2.1.3. Sphingomyelin
2.1.4. Glycosphingolipids
2.1.5. Ceramide-1-Phosphate
2.1.6. Sphingosine-1-Phosphate
2.2. Physiological Roles of Sphingolipids
2.2.1. Sphingoid Bases
2.2.2. Ceramides
2.2.3. Sphingomyelin
2.2.4. Glycosphingolipids
2.2.5. Ceramide-1-Phosphate
2.2.6. Sphingosine-1-Phosphate
3. Sphingolipids and Vascular Disease
3.1. Sphingolipids and Atherosclerosis
3.2. Sphingolipids and Aneurysmal Disease
3.3. Sphingolipids and Stroke
4. Sphingolipids and Myocardial Disease
4.1. Sphingolipids and Heart Failure
4.2. Sphingolipids and Atrial Fibrillation
5. Sphingolipids and Metabolic Disease
6. Sphingolipids as a Therapeutic Target
6.1. Weight Loss and Exercise
6.2. Dietary Interventions
6.2.1. Oleic Acid
6.2.2. Milk Polar Lipids
6.2.3. Ginseng
6.2.4. Low-Fat and Low-Carbohydrate Diet
6.3. Pharmacological Treatments
6.3.1. Fingolimod
6.3.2. Statins
6.3.3. Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists
6.3.4. Sodium Glucose Transporter 2 (SGLT-2) Inhibitors
6.3.5. Amitriptyline
6.3.6. Desipramine
6.3.7. N-Acetylcysteine
6.3.8. SPT Inhibitors
6.3.9. SphK Inhibitors
6.3.10. UDP-Glucose Ceramide Glucosyltransferase Inhibitors
6.3.11. Dihydroceramide DES Inhibitors
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Ac-CDase: | Acid Ceramidase |
Ac-SMase: | Acid Sphingomyelinase |
AF: | Atrial Fibrillation |
Ak-CDase: | Alkaline Ceramidase |
Ak-SMase: | Alkaline Sphingomyelinase |
AMPK: | AMP-activated Protein Kinase |
ANP: | Atrial Natriuretic Peptide |
ApoE: | Apolipoprotein E |
ApoM: | Apolipoprotein M |
BCL-2: | B-cell Lymphoma 2 |
BMI: | Body Mass Index |
BNP: | Brain Natriuretic Peptide |
C1P: | Ceramide-1-Phosphate |
C1PP: | C1P phosphatase |
CDase: | Ceramidase |
CerK: | Ceramide Kinase |
CerS: | Ceramide Synthase |
CNS: | Central Nervous Systems |
CoA: | Co-enzyme A |
COX2: | Cyclooxygenase 2 |
CVD: | Cardiovascular Disease |
DES1: | Desaturase 1 |
D-PDMP: | D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol |
eNOS: | Endothelial Nitric Oxide Synthase |
ER: | Endoplasmic Reticulum |
FFA: | Free Fatty Acids |
GLP-1R: | Glucagon-like Peptide-1 Receptor |
GM1: | Monosialotetrahexosylganglioside |
GM3: | Monosialodihexosylganglioside |
HCASMCs: | Human Coronary Artery Smooth Muscle Cells |
HDL: | High-Density Lipoprotein Cholesterol |
HF: | Heart Failure |
HFpEF: | Heart Failure with Preserved Ejection Fraction |
HFrEF: | Heart Failure with Reduced Ejection Fraction |
HOA: | High Oleic Acid Diet |
HOMAIR: | Homeostatic Model Assessment of Insulin Resistance |
HPA: | High Palmitic Acid Diet |
HUVECs: | Human Umbilical Vein Endothelial Cells |
IHD: | Ischaemic Heart Disease |
IL-1β: | Interleukin-1β |
IL-6: | Interleukin 6 |
JNK: | c-Jun N-terminal Kinase |
LDL: | Low-Density Lipoprotein Cholesterol |
LDL-R: | LDL receptor |
LVEF: | Left Ventricular Ejection Fraction |
MACE: | Major Adverse Cardiovascular Events |
MCP-1: | monocyte chemoattractant protein-1 |
MI: | Myocardial Infarction |
MMPs: | Matrix Metalloproteinases |
MPLs: | Milk Polar Lipids |
MSM: | Milk Sphingomyelin |
NADPH: | Nicotinamide Adenine Dinucleotide Phosphate |
NF-κB: | Nuclear Factor Kappa Beta |
NKT: | Natural Killer T Cell |
NO: | Nitric Oxide |
NOX: | NADPH Oxidase |
N-CDase: | Neutral Ceramidase |
N-SMase: | Neutral Sphingomyelinase |
Ox-LDL: | Oxidised LDL |
PAI-1: | Plasminogen Activator Inhibitor 1 |
PCSK9: | Protein Convertase Subtilisin/Kexin Type 9 |
PI3K: | Phosphatidylinositol 3-Kinase |
PKC: | Protein Kinase C |
PNS: | Peripheral Nervous System |
PP2A: | Protein Phosphatase 2A |
RANTES: | Regulated on Activation, Normal T Cell Expressed and Secreted |
RCT: | Randomised Control Trial |
ROS: | Reactive Oxygen Species |
RYGB: | Roux-en-Y Gastric Bypass |
S1P: | Sphingosine-1-Phosphate |
S1PP: | S1P Phosphatase |
S1PR1-5: | S1P Receptors 1-5 |
SFA: | Saturated Fatty Acid |
SGLT-2: | Sodium Glucose Transporter 2 |
SMase: | Sphingomyelinase |
SMS: | Sphingomyelin synthase |
SphK: | Sphingosine Kinase |
SPL: | Sphingosine-1-Phosphate Lyase |
SPT: | Serine Palmitoyltransferase |
T1DM: | Type 1 Diabetes Mellitus |
TACE: | TNFα-Converting Enzyme |
TCA: | Tri-cyclic Antidepressant |
TLR4: | Toll-like Receptor 4 |
TNFα: | Tumour Necrosis Factor Alpha |
UDP: | Uridine Diphosphate |
UFA: | Unsaturated Fatty Acid |
UGal-CG: | UDP-Galactose Ceramide Galactosyltransferase |
UGlu-CG: | UDP-Glucose Ceramide Glucosyltransferase |
VEGFR2: | Vascular Endothelial Growth Factor Receptor 2 |
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Sphingolipid Species | Effect on Cardiovascular Physiology and Pathophysiology | ||||||
---|---|---|---|---|---|---|---|
Atherosclerosis | Endothelial Dysfunction | Dyslipidaemia | Inflammation and Immune Modulation | Oxidative Stress | Tissue Death/ Remodelling | Insulin Resistance | |
Ceramide | - Increased levels in atherosclerotic plaques. - Increased levels in acute ischaemic and haemorrhagic stroke brain tissue as well as in the reperfusion period. - Accumulates in the ischaemic core and peri-ischaemic brain regions. | - Induces eNOS uncoupling and reduced NO bioavailability - Promotes vasoconstriction and increased vascular permeability. - Induces mitochondrial permeability which triggers caspase activation and endothelial cell apoptosis. - Induces VSMC apoptosis and contributes to aneurysm formation. - Induces cerebral vasoconstriction and leukocyte adhesion, predisposing to herald bleeds. Increased levels associated with increased systolic blood pressure. | - Positively correlates with total cholesterol and LDL. - Conversion of LDL membrane Sphingomyelin to Ceramide leads to hydrophobic LDL particles and increased LDL aggregation. - Stabilises endothelial membrane rafts containing Lox-1, Cavin-1, and Caveolin-1, responsible for Ox-LDL internalisation. | - Increased plaque levels associated with raised MCP-1 and IL-6. - Endothelial cell Ceramide generation enhanced by TNFα. - Increased intracellular Ceramide associated with increased adhesion molecule expression in monocytes, and lead to increased vascular adhesion, OxLDL internalisation and foam cell formation. - Promote myocardial immune cell infiltration and inflammation leading to diminished cardiac function. | - Upregulates NOX and eNOS-mediated ROS production. - Enhances mitochondrial ROS production through disruption of the electron transport chain. - ROS production leads to cell damage and apoptosis. - Ceramide upregulated by ROS-mediated SMase activation. | - Hypoxia upregulates SPT activity, increases Ceramide synthesis, increasing apoptosis. - Increased C16 Ceramide associated with adverse cardiac remodelling. - De novo synthesis upregulated in failing cardiac tissue. Accumulation leads to cardiomyocyte apoptosis. | - Increased in obesity and positively correlated with waist circumference, BMI and HOMAIR. - C24 Ceramide replacement my be metabolically beneficial, increasing weight loss, insulin sensitivity, glucose tolerance, and FFA oxidation. - Directly and indirectly inhibit phosphorylation of Akt thereby impairing cellular insulin signalling, causing insulin resistance. - Accumulates in the pancreas in T2DM. |
Dihydroceramide | - Increased levels in advanced atherosclerotic plaques. | - Increased plaque levels associated with raised MCP-1 and IL-6. | |||||
Sphingomyelin | - Increased levels in advanced atherosclerotic plaques. | - Reduces intestinal cholesterol absorption, ameliorating hyperlipidaemia. | - Increased plaque levels associated with raised MCP-1 and IL-6. | ||||
Sphingosine 1-Phosphate | - Can induce vasoconstriction and increased vascular permeability at supraphysiological concentrations. - Reduces eNOS activity and NO bioavailability. - Triggers assembly of endothelial adherens junctions and stabilisation of existing junctions ensuring preservation of endothelial barrier function. - Promotes endothelial cell proliferation and survival. | - Levels positively correlated with total cholesterol and LDL. | - Increased plaque levels associated with raised TNFα and RANTES. - Upregulates lymphocyte activation, adhesion molecule expression, and intimal migration. - Upregulates endothelial adhesion molecule expression. - Binds to ApoM-HDL in the circulation and, through this association, inhibits TNFα-induced NF-κB signalling and endothelial adhesion molecule expression. - Can upregulate endothelial COX2 expression and subsequent prostaglandin E2 secretion through S1PR3 signalling. - Associated with reduced myocardial inflammation. | - Associated with lower prevalence of aneurysmal disease. - Associated with reduced myocardial remodelling. - Promotes cardiac fibrosis (as a result of overexpression of SphK and S1PR1&3). - HDL-S1P reduces IL-1β-induced β-islet apoptosis. | - S1PR2 (responsible for atherogenic effects) is upregulated in hyperglycaemia. - Levels increased in obesity and positively correlated with waist circumference, BMI, and HOMAIR. - S1PR activation upregulates Akt phosphorylation, improving insulin signalling and enhancing β-islet survival in T1DM. | ||
Ceramide-1-Phosphate | - May promote neointima formation and endothelial repair. | - Inhibits cigarette smoke-induced inflammation by downregulating TNFα, 1L-1β, and IL-6 expression. - Has paradoxically also been shown to activate TNFα, IL-6, and phospholipase A2 to promote prostaglandin synthesis. | - Activates MMP2 and MMP9 leading to aortic matrix destruction. | ||||
Glucosylceramide | - Accumulates in the intima of atherosclerotic plaques. - Increased levels in advanced atherosclerotic plaques. - Purported anticoagulant effect may be protective. - Levels of complex gangliosides diminish and simple gangliosides increase in brain tissue subjected to hypoxic ischaemia. | - Induces VSMC apoptosis. | - Increased plaque levels associated with raised MCP-1 and IL-6. - Stimulates VSMC MIP-1β, TNFα, MCP-1, and RANTES secretion. - Plaque levels positively correlated with plaque CD68 macrophage levels. | - Conversion of simple to complex gangliosides in ischaemic tissue leads to increased tissue damage, increased neuronal death, and diminished neurological recovery. | - Directly act on the insulin receptor to impair cellular insulin signalling, causing insulin resistance. - GM3 is an especially potent inhibitor of inulin signalling. | ||
Galactosylceramide | - Levels of complex gangliosides diminish and simple gangliosides increase in brain tissue subjected to hypoxic ischaemia. | - Plaque levels positively correlated with plaque CD68 macrophage levels. | - Conversion of simple to complex gangliosides in ischaemic tissue leads to increased tissue damage, increased neuronal death, and diminished neurological recovery. | ||||
Lactosylceramide | - Accumulates in the intima of atherosclerotic plaques. - Increased levels in advanced atherosclerotic plaques. - Promotes VSMC proliferation, aiding fibrous cap formation. - Levels of complex gangliosides diminish and simple gangliosides increase in brain tissue subjected to hypoxic ischaemia. | - Increased plaque levels associated with raised MCP-1 and IL-6. - Plaque levels positively correlated with plaque CD68 macrophage levels. - Upregulates endothelial cell expression of NF-κB and ICAM-1. | - Conversion of simple to complex gangliosides in ischaemic tissue leads to increased tissue damage, increased neuronal death, and diminished neurological recovery. |
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Foran, D.; Antoniades, C.; Akoumianakis, I. Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target? Nutrients 2024, 16, 3296. https://doi.org/10.3390/nu16193296
Foran D, Antoniades C, Akoumianakis I. Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target? Nutrients. 2024; 16(19):3296. https://doi.org/10.3390/nu16193296
Chicago/Turabian StyleForan, Daniel, Charalambos Antoniades, and Ioannis Akoumianakis. 2024. "Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target?" Nutrients 16, no. 19: 3296. https://doi.org/10.3390/nu16193296
APA StyleForan, D., Antoniades, C., & Akoumianakis, I. (2024). Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target? Nutrients, 16(19), 3296. https://doi.org/10.3390/nu16193296