MLN4924 Treatment Diminishes Excessive Lipid Storage in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease (NAFLD) by Stimulating Hepatic Mitochondrial Fatty Acid Oxidation and Lipid Metabolites
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Cell Culture and Lipid Droplet Induction
2.3. Western Blotting
2.4. Mitochondria, Bodipy and DAPI Staining
2.5. Isolation of Mouse Primary Hepatocyte
2.6. Liver Triglyceride Extraction
2.7. Small Animal NMR Analyzer and Metabolic Cages Measurements
2.8. Fatty Acid Oxidase Testing
2.9. Statistics
3. Results
3.1. Prolonged Exposure to Free Fatty Acid Can Induce Lipid Accumulation in Primary Hepatocytes
3.2. Neddylation Inhibitor MLN4924 Can Prevent Lipid Accumulation Induced by FFA in Hepatocytes
3.3. MLN4924 Treatment Protected HFD-Fed Mice from Developmenting of NAFLD and Obesity
3.4. MLN4924 Limits Lipid Accumulation and the Size of Lipid Droplets in Metabolic Tissues
3.5. MLN4924 Promotes O2 Consumption, CO2 Production and Thermogenesis in HFD-Induced NAFLD Mice Model
3.6. MLN4924 Inhibits Neddylation, Elevates Hepatic Fatty Acid Oxidase Levels, and Reduces Hepatic Triglyceride Levels in HFD-Induced NAFLD Mice Model
3.7. Lipidomics Analysis Uncovered Differences in Lipid Metabolites from Liver Cells Treated with MLN4924
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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HMDB ID | log2fold | p-Value | Up/Down | m/z | Description |
---|---|---|---|---|---|
HMDB0001904 | −22.012587 | 0.048762 | Down | 244.0920 | 3-Nitrotyrosine |
HMDB0012243 | −7.299020 | 0.000100 | Down | 395.1660 | Kinetin-7-N-glucoside |
HMDB0014592 | −4.649321 | 0.042829 | Down | 352.2106 | Dipivefrin |
HMDB0013222 | −3.586083 | 0.027941 | Down | 132.0766 | Beta-Guanidinopropionic acid |
HMDB0001212 | −3.212516 | 0.034643 | Down | 217.0474 | Hydantoin-5-propionic acid |
HMDB0038968 | −2.893064 | 0.015947 | Down | 281.0355 | 1-Propenyl 1-(1-propenylsulfinyl)propyl disulfide |
HMDB0036650 | −2.275692 | 0.019872 | Down | 325.0318 | Sinalbin A |
HMDB0015269 | −2.131924 | 0.014434 | Down | 427.1073 | Sulfinpyrazone |
HMDB0034364 | −1.790339 | 0.000586 | Down | 304.0628 | Cepharadione A |
HMDB0003040 | −1.719765 | 0.023093 | Down | 267.0731 | Arabinosylhypoxanthine |
HMDB0041468 | −1.685299 | 0.000997 | Down | 302.0658 | 1,3,5-Trihydroxy-10-methylacridone |
HMDB0034364 | −1.607278 | 0.001931 | Down | 304.0629 | Cepharadione A |
HMDB0000296 | −1.520245 | 0.011211 | Down | 243.0616 | Uridine |
HMDB0014340 | −1.508761 | 0.000539 | Down | 312.0947 | Vidarabine |
HMDB0032852 | −1.483694 | 0.010759 | Down | 241.0825 | 2-(Ethylamino)-4,5-dihydroxybenzamide |
HMDB0038968 | −1.446022 | 0.027435 | Down | 281.0356 | 1-Propenyl 1-(1-propenylsulfinyl)propyl disulfide |
HMDB0040795 | 1.033134 | 0.000000 | Up | 347.1854 | 7′-O-Methylmarmin |
HMDB0057488 | 1.279045 | 0.010018 | Up | 1373.9427 | CL(16:1(9Z)/16:1(9Z)/18:1(11Z)/16:1(9Z)) |
HMDB0040795 | 1.291746 | 0.000001 | Up | 347.1855 | 7′-O-Methylmarmin |
HMDB0004886 | 1.389978 | 0.001551 | Up | 1158.7890 | Trihexosylceramide (d18:1/24:0) |
HMDB0014902 | 1.420620 | 0.000000 | Up | 444.1687 | Mometasone |
HMDB0009422 | 1.451045 | 0.016616 | Up | 810.5281 | PE(20:4(8Z,11Z,14Z,17Z)/18:1(9Z)) |
HMDB0015621 | 1.562168 | 0.000135 | Up | 328.1063 | Sulfadimethoxine |
HMDB0012389 | 1.584051 | 0.002586 | Up | 812.5430 | PS(18:1(9Z)/18:0) |
HMDB0009090 | 1.610539 | 0.019622 | Up | 788.5444 | PE(18:2(9Z,12Z)/18:0) |
HMDB0010660 | 1.839512 | 0.004755 | Up | 762.5259 | PG(18:3(6Z,9Z,12Z)/16:0) |
HMDB0010661 | 1.893689 | 0.006705 | Up | 760.5106 | PG(18:3(6Z,9Z,12Z)/16:1(9Z)) |
HMDB0010662 | 1.894613 | 0.005903 | Up | 790.5562 | PG(18:3(6Z,9Z,12Z)/18:0) |
HMDB0012378 | 2.180602 | 0.002500 | Up | 814.5566 | PS(18:0/18:0) |
HMDB0014761 | 2.250722 | 0.000000 | Up | 460.1635 | Fluphenazine |
HMDB0012356 | 2.319175 | 0.006175 | Up | 786.5241 | PS(16:0/18:0) |
HMDB0010624 | 2.361055 | 0.002972 | Up | 816.5743 | PG(18:1(11Z)/20:3(8Z,11Z,14Z)) |
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Ge, M.; Huang, L.; Ma, Y.; Sun, S.; Wu, L.; Xu, W.; Yang, D. MLN4924 Treatment Diminishes Excessive Lipid Storage in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease (NAFLD) by Stimulating Hepatic Mitochondrial Fatty Acid Oxidation and Lipid Metabolites. Pharmaceutics 2022, 14, 2460. https://doi.org/10.3390/pharmaceutics14112460
Ge M, Huang L, Ma Y, Sun S, Wu L, Xu W, Yang D. MLN4924 Treatment Diminishes Excessive Lipid Storage in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease (NAFLD) by Stimulating Hepatic Mitochondrial Fatty Acid Oxidation and Lipid Metabolites. Pharmaceutics. 2022; 14(11):2460. https://doi.org/10.3390/pharmaceutics14112460
Chicago/Turabian StyleGe, Mengxiao, Linlin Huang, Yinjun Ma, Shuangyi Sun, Lijun Wu, Wei Xu, and Dongqin Yang. 2022. "MLN4924 Treatment Diminishes Excessive Lipid Storage in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease (NAFLD) by Stimulating Hepatic Mitochondrial Fatty Acid Oxidation and Lipid Metabolites" Pharmaceutics 14, no. 11: 2460. https://doi.org/10.3390/pharmaceutics14112460
APA StyleGe, M., Huang, L., Ma, Y., Sun, S., Wu, L., Xu, W., & Yang, D. (2022). MLN4924 Treatment Diminishes Excessive Lipid Storage in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease (NAFLD) by Stimulating Hepatic Mitochondrial Fatty Acid Oxidation and Lipid Metabolites. Pharmaceutics, 14(11), 2460. https://doi.org/10.3390/pharmaceutics14112460