Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets
Abstract
:1. Introduction
2. Ceramides
Ceramides in NAFLD-ATS Development
3. Ceramides as Potential Biomarkers in Atherosclerosis Related Diseases
4. Ceramides as Potential Therapeutic Targets
4.1. Myriocin
4.2. CerS Inhibitors
4.3. Des1 Inhibitors
4.4. MTP Inhibitors
4.5. ASMase Inhibitors
4.6. Lip-C6
4.7. Glucagon-like Peptide-1 (GLP-1)
4.8. Intestinal FXR/SMPD3 Axis
4.9. Other Therapeutic Approaches
Main Focus | Species | Outcomes | Year | Ref. |
---|---|---|---|---|
Fumonisine B1 | Mice | 60% reduction of hepatic SM levels (p < 0.05), increase expression of hepatic SPT (p < 0.01); SPHK 1 maximal at the lowest dose of 0.75 mg/kg (p < 0.05), expression of SPHK2 not affected; | 2006 | [92] |
Elovl6 | Mice | Reduced: Ceramide(d18:1/18:0)(0.63, p < 0.001); ceramide (d18:2/18:0) (1.68, p < 0.05), oleate (C18:1n-9) and stearate (C18:0); | 2020 | [150] |
CerS2 | Mice | Reduced lipid accumulation, sphingomyelin levels ~50%, uptake in the liver, reduction in very long chain acyl ceramides, enzymatic activity-decreased; | 2015 | [151] |
CerS6 | Mice | Reduce C16:0 ceramides, serum insulin concentrations, protects from macrophage infiltration, activation of pro-inflammatory gene expression; improve glucose tolerance and insulin sensitivity; reduced adiposity and increased energy expenditure, (p < 0.05); | 2014 | [152] |
Diet | Human | Ceramides C22:0, C24:1; C26:0 reduced-29%, (p < 0.05), C24:0 50%, (p < 0.01); at week 8 increase of C16:0 (p < 0.05); | 2017 | [76] |
P053 | Mice | 5 mg/kg/day reduced C18 ceramide by 31%, (p < 0.01); Reduces whole-body fat mass and the weight of white adipose depots; | 2018 | [17] |
GW4869 | Mice | Decrease of: the atherosclerotic area, accumulation of macrophages by 68%; atherosclerotic lesions by 69% (p < 0.001), in plasma Cer24:1, Cer22:0, and Cer24:0, (p < 0.05), lipid accumulation by 68% (p < 0.01); | 2018 | [121] |
CerS1 | Mice | The sphingolipid content in heart, liver, and white adipose tissue—not affect, imprivement of liver glucose metabolism, 95% reduction in C18:0 ceramide; | 2019 | [153] |
CerS5 | Mice | Improves glucose tolerance, insulin sensitivity, reduces white adipose inflammation, In skeletal muscle without obvious decrease; | 2019 | [153] |
Bortezomib | Mice | Increase hepatic CerS2 expression, protects from development of NAFLD, decreases weight gain, TG levels lower (p < 0.01); | 2019 | [154] |
Exendin-4 | Mice | Decrease lobular inflammation (p = 0.18), fibrosis stages (p = 0.24) | 2019 | [155] |
DEGS1 gene | Mice | Decreased: Cer16:0–0.09, Cer18:0–0.1 (p < 0.001), whole-body insulin sensitivity-restored, selective insulin resistance-reversed in the liver (p < 0.001); | 2019 | [115] |
Myriocin | Rats | Reduced: serum ceramide content reduced, (p < 0.05), hepatic triglyceride, ALT, AST, hepatic inflammation, amount of inflammatory cell; Bcl-2 expression restored, (p < 0.05); | 2019 | [87] |
Fenretinide | Mice | Lowered: plaque area 50.8% (p < 0.05), plasma lipid levels by 20.1%, (p < 0.05), and plasma ceramides; | 2020 | [156] |
Diet | Mice | Flinax reduced lipoperoxidation markers, hepatic fat accumulation restores complex I, III, V (ATP-synthase), lower peroxides levels, (p < 0.05), no difference in complex IV, and higher production of CPT1A and CPT2; | 2021 | [148] |
Alpha-mangostin | Mice | Inhibits: ceramide content, and, Inhibites aSMase activity, | 2021 | [146] |
Farnesoid X receptor | Mice | Lower: ceramide content, hepatic cholesterol levels, mRNA levels of Smpd3 elevates hepatic Cyp7a1 mRNA levels Repressed lesion areas in aortas and smaller atherosclerotic lesions; | 2021 | [120] |
Liraglutide | Mice | Gene expression Sptlc2, cerS4, and cerS6 decreased; C16 and C24 accumulation was limited (p < 0.05); Unchanged: saturated fatty acid, phospholipids with long chains-reduced, phospholipids with very long chains | 2021 | [132] |
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Ceramide Synthases (CerS) | Tissue Distribution | Acyl-CoA Specificity | The Biophysical Properties | Ref. |
---|---|---|---|---|
CerS 1 | Brain Skeletal muscle | C18, C18:1 | Play important roles in signaling and sphingolipid development; Promotes insulin resistance in humans; | [16,17] |
CerS 2 | Liver Kidney | C20, C22,C24, C24:1, C26 | Play vital roles in postnatal liver development and physiology; Have major molecular roles in the maintenance of normal liver homeostasis; | [18,19] |
CerS 3 | Intestine Skin Testes | C18, C18:1,C20, C22, C24, C24:1 | Maintain the water permeability barrier function; Involved in sperm formation and androgen production; | [20,21] |
CerS 4 | Heart Liver | C18, C20 | Highly expressed in liver cancer tissues and can facilitate HCC (Hepatocellular Carcinoma) formation; Controls homeostatic epidermal barrier maintenance; | [22,23] |
CerS 5 | Lung Prostate Thymus Spleen Skeletal muscle | C14, C16, C18, C18:1 | Contributes to the development of diet-induced obesity; Play roles in sphingosine salvage pathway signaling and in the response to cellular stress; | [24,25] |
CerS 6 | Lymph node Intestine | C14, C16, C18 | May serve as biomarkers in determining the effectiveness of anticancer agents; C16:0 is a significant factor in the development of obesity and its related complications. | [26,27] |
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Tanase, D.M.; Gosav, E.M.; Petrov, D.; Jucan, A.E.; Lacatusu, C.M.; Floria, M.; Tarniceriu, C.C.; Costea, C.F.; Ciocoiu, M.; Rezus, C. Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets. Diagnostics 2021, 11, 2053. https://doi.org/10.3390/diagnostics11112053
Tanase DM, Gosav EM, Petrov D, Jucan AE, Lacatusu CM, Floria M, Tarniceriu CC, Costea CF, Ciocoiu M, Rezus C. Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets. Diagnostics. 2021; 11(11):2053. https://doi.org/10.3390/diagnostics11112053
Chicago/Turabian StyleTanase, Daniela Maria, Evelina Maria Gosav, Daniela Petrov, Alina Ecaterina Jucan, Cristina Mihaela Lacatusu, Mariana Floria, Claudia Cristina Tarniceriu, Claudia Florida Costea, Manuela Ciocoiu, and Ciprian Rezus. 2021. "Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets" Diagnostics 11, no. 11: 2053. https://doi.org/10.3390/diagnostics11112053
APA StyleTanase, D. M., Gosav, E. M., Petrov, D., Jucan, A. E., Lacatusu, C. M., Floria, M., Tarniceriu, C. C., Costea, C. F., Ciocoiu, M., & Rezus, C. (2021). Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets. Diagnostics, 11(11), 2053. https://doi.org/10.3390/diagnostics11112053