{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T16:25:51Z","timestamp":1787588751924,"version":"build-2736575974"},"reference-count":64,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T00:00:00Z","timestamp":1668470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770579"],"award-info":[{"award-number":["81770579"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970506"],"award-info":[{"award-number":["81970506"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>MLN4924 is a selective neddylation inhibitor that has shown great potential in treating several cancer and metabolic diseases, including obesity. However, it remains largely unknown whether MLN4924 has similar effect on non-alcoholic liver disease (NAFLD), which is closely associated with metabolic disorders. Here, we investigated the role of MLN4924 in NAFLD treatment and the underlying mechanism of the action using primary hepatocytes stimulated with free fatty acid, as well as high-fat diet (HFD)-induced NAFLD mouse models. We found that MLN4924 can inhibit the accumulation of lipid and reduce the expression of peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3), a key player in adipocyte differentiation and function in both in vivo and in vitro models. Moreover, we verified its important role in decreasing the synthesis and accumulation of fat in the liver, thus mitigating the development of NAFLD in the mouse model. The body weight and fat mass in MLN4924-treated animals were significantly reduced compared to the control group, while the metabolic activity, including O2 consumption, CO2 and heat production, also increased in these animals. Importantly, we demonstrated for the first time that MLN4924 can markedly boost mitochondrial fat acid oxidation (FAO) to alter liver lipid metabolism. Finally, we compared the metabolites between MLN4924-treated and untreated Huh7 cells after fatty acid induction using lipidomics methods and techniques. We found induction of several metabolites in the treated cells, including Beta-guanidinopropionic acid (b-GPA) and Fluphenazine, which was in accordance with the increase of FAO and metabolism. Together, our study provided a link between neddylation modification and energy metabolism, as well as evidence for targeting neddylation as an emerging therapeutic approach to tackle NAFLD.<\/jats:p>","DOI":"10.3390\/pharmaceutics14112460","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:31:27Z","timestamp":1668565887000},"page":"2460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["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"],"prefix":"10.3390","volume":"14","author":[{"given":"Mengxiao","family":"Ge","sequence":"first","affiliation":[{"name":"Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinjun","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Library, Fudan University, 220 Handan Road, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0126-5898","authenticated-orcid":false,"given":"Dongqin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1007\/s00018-018-2860-6","article-title":"Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease","volume":"75","author":"Ipsen","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/S0140-6736(20)32511-3","article-title":"Non-alcoholic fatty liver disease","volume":"397","author":"Powell","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S2213-8587(18)30154-2","article-title":"Non-alcoholic fatty liver disease: Causes, diagnosis, cardiometabolic consequences, and treatment strategies","volume":"7","author":"Stefan","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1146\/annurev-med-051215-031109","article-title":"Nonalcoholic Steatohepatitis","volume":"68","author":"Suzuki","year":"2017","journal-title":"Annu. Rev. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.2337\/db21-0999","article-title":"CHCHD10 Modulates Thermogenesis of Adipocytes by Regulating Lipolysis","volume":"71","author":"Ding","year":"2022","journal-title":"Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"884601","DOI":"10.3389\/fbioe.2022.884601","article-title":"Silk Hydrogel-Mediated Delivery of Bone Morphogenetic Protein 7 Directly to Subcutaneous White Adipose Tissue Increases Browning and Energy Expenditure","volume":"10","author":"Townsend","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"bvab024","DOI":"10.1210\/jendso\/bvab024","article-title":"Removal of Epididymal Visceral Adipose Tissue Prevents Obesity-Induced Multi-organ Insulin Resistance in Male Mice","volume":"5","author":"Franczyk","year":"2021","journal-title":"J. Endocr. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100332","DOI":"10.1016\/j.xcrm.2021.100332","article-title":"Brown adipose tissue is associated with healthier body fat distribution and metabolic benefits independent of regional adiposity","volume":"2","author":"Wibmer","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1002\/hep.31881","article-title":"Hepatic Small Ubiquitin-Related Modifier (SUMO)-Specific Protease 2 Controls Systemic Metabolism Through SUMOylation-Dependent Regulation of Liver-Adipose Tissue Crosstalk","volume":"74","author":"Liu","year":"2021","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6130","DOI":"10.1093\/nar\/gkz312","article-title":"Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation","volume":"47","author":"Song","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4477","DOI":"10.1172\/JCI127374","article-title":"Degradation of splicing factor SRSF3 contributes to progressive liver disease","volume":"129","author":"Kumar","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/hep.28933","article-title":"Deregulated Neddylation in Liver Fibrosis","volume":"65","author":"Simon","year":"2017","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12964-020-00576-z","article-title":"Neddylation inhibition activates the protective autophagy through NF-kappa B-catalase-ATF3 Axis in human esophageal cancer cells","volume":"18","author":"Liang","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10637-016-0348-5","article-title":"A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924\/MLN4924) in patients with metastatic melanoma","volume":"34","author":"Bhatia","year":"2016","journal-title":"Investig. New Drug"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/bjh.13323","article-title":"Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: A phase 1 study","volume":"169","author":"Swords","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1158\/1078-0432.CCR-15-1237","article-title":"Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed\/Refractory Multiple Myeloma or Lymphoma","volume":"22","author":"Shah","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/978-981-15-1025-0_21","article-title":"Neddylation-Independent Activities of MLN4924","volume":"1217","author":"Mao","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13578-021-00569-6","article-title":"Neddylation regulation of mitochondrial structure and functions","volume":"11","author":"Zhou","year":"2021","journal-title":"Cell Biosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3360","DOI":"10.1158\/0008-5472.CAN-12-0388","article-title":"The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth","volume":"72","author":"Luo","year":"2012","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1517\/13543784.2012.707192","article-title":"MLN4924: A novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy","volume":"21","author":"Nawrocki","year":"2012","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.cellsig.2018.01.009","article-title":"Protein neddylation and its alterations in human cancers for targeted therapy","volume":"44","author":"Zhou","year":"2018","journal-title":"Cell Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/j.bbamcr.2017.05.009","article-title":"Cul3 neddylation is crucial for gradual lipid droplet formation during adipogenesis","volume":"1864","author":"Dubiel","year":"2017","journal-title":"Biochim. Biophys. Acta-Mol. Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1038\/cdd.2016.6","article-title":"PPARgamma neddylation essential for adipogenesis is a potential target for treating obesity","volume":"23","author":"Park","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/s41569-021-00569-6","article-title":"PPAR control of metabolism and cardiovascular functions","volume":"18","author":"Montaigne","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1146\/annurev.biochem.77.061307.091829","article-title":"Fat and Beyond: The Diverse Biology of PPAR\u03b3","volume":"77","author":"Tontonoz","year":"2008","journal-title":"Annu. Rev. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/bcpt.13190","article-title":"A role of peroxisome proliferator-activated receptor gamma in non-alcoholic fatty liver disease","volume":"124","author":"Lykkesfeldt","year":"2019","journal-title":"Basic Clin. Pharm. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"653882","DOI":"10.3389\/fcell.2021.653882","article-title":"Advances in Cancer Treatment by Targeting the Neddylation Pathway","volume":"9","author":"Gai","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1210\/er.2019-00034","article-title":"The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance","volume":"40","author":"Watt","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Fujii, H., Kawada, N., and Japan Study Group of NAFLD (JSG-NAFLD) (2020). The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113863"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.celrep.2019.06.016","article-title":"Innate Lymphoid Cells in the Induction of Obesity","volume":"28","author":"Sasaki","year":"2019","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/s41574-021-00562-6","article-title":"The evolving view of thermogenic adipocytes\u2014Ontogeny, niche and function","volume":"17","author":"Shamsi","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2337\/db21-0363","article-title":"Hepatic CPT1A Facilitates Liver\u2013Adipose Cross Talk via Induction of FGF21 in Mice","volume":"71","author":"Sun","year":"2022","journal-title":"Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e13192","DOI":"10.14814\/phy2.13192","article-title":"Beta-GPA treatment leads to elevated basal metabolic rate and enhanced hypoxic exercise tolerance in mice","volume":"5","author":"Ross","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1203\/00006450-198712000-00027","article-title":"Peroxisomal Proliferation in Heart and Liver of Mice Receiving Chlorpromazine, Ethyl 2(5(4-Chlorophenyl)Pentyl) Oxiran-2-Carboxylic Acid or High-Fat Diet\u2014A Biochemical and Morphometrical Comparative-Study","volume":"22","author":"Vamecq","year":"1987","journal-title":"Pediatr. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1039\/D0FO02533J","article-title":"Uridine attenuates obesity, ameliorates hepatic lipid accumulation and modifies the gut microbiota composition in mice fed with a high-fat diet","volume":"12","author":"Liu","year":"2021","journal-title":"Food Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"586881","DOI":"10.3389\/fmed.2020.586881","article-title":"Neddylation: A Versatile Pathway Takes on Chronic Liver Diseases","volume":"7","author":"Yao","year":"2020","journal-title":"Front. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lachiondo-Ortega, S., Mercado-Gomez, M., Serrano-Macia, M., Lopitz-Otsoa, F., Salas-Villalobos, T.B., Varela-Rey, M., Delgado, T.C., and Martinez-Chantar, M.L. (2019). Ubiquitin-Like Post-Translational Modifications (Ubl-PTMs): Small Peptides with Huge Impact in Liver Fibrosis. Cells, 8.","DOI":"10.3390\/cells8121575"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nature07884","article-title":"An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer","volume":"458","author":"Soucy","year":"2009","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.4161\/auto.22024","article-title":"Protective autophagy induced by RBX1\/ROC1 knockdown or CRL inactivation via modulating the DEPTOR-MTOR axis","volume":"8","author":"Yang","year":"2012","journal-title":"Autophagy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.cell.2008.07.022","article-title":"Structural insights into NEDD8 activation of cullin-RING ligases: Conformational control of conjugation","volume":"134","author":"Duda","year":"2008","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.18632\/oncotarget.3191","article-title":"Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer","volume":"6","author":"Delgado","year":"2015","journal-title":"Oncotarget"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.biocel.2017.12.019","article-title":"Mitochondria in non-alcoholic fatty liver disease","volume":"95","author":"Simoes","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7283639","DOI":"10.1155\/2019\/7283639","article-title":"MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury","volume":"2019","author":"Yu","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"101765","DOI":"10.1016\/j.redox.2020.101765","article-title":"The necessity of NEDD8\/Rub1 for vitality and its association with mitochondria-derived oxidative stress","volume":"37","author":"Pick","year":"2020","journal-title":"Redox Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nrm4074","article-title":"Transcriptional regulation of hepatic lipogenesis","volume":"16","author":"Wang","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41419-020-2472-6","article-title":"Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment","volume":"11","author":"Ju","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e121582","DOI":"10.1172\/jci.insight.121582","article-title":"Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells","volume":"4","author":"Zhou","year":"2019","journal-title":"JCI Insight"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev-pathmechdis-012419-032711","article-title":"Mitochondrial Dynamics and Its Involvement in Disease","volume":"15","author":"Chan","year":"2020","journal-title":"Annu. Rev. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.bbadis.2016.11.010","article-title":"Mitochondrial dysfunction and oxidative stress in metabolic disorders\u2014A step towards mitochondria based therapeutic strategies","volume":"1863","author":"Bhatti","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1007\/s00018-021-03775-0","article-title":"Mitochondrial quality control: From molecule to organelle","volume":"78","author":"Tait","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11906-017-0710-9","article-title":"Role of Mitochondrial Dysfunction in Hypertension and Obesity","volume":"19","author":"Lahera","year":"2017","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"102336","DOI":"10.1016\/j.ceca.2020.102336","article-title":"Role of mitochondria in liver metabolic health and diseases","volume":"94","author":"Morio","year":"2021","journal-title":"Cell Calcium"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Doblado, L., Lueck, C., Rey, C., Samhan-Arias, A.K., Prieto, I., Stacchiotti, A., and Monsalve, M. (2021). Mitophagy in Human Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083903"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2018.11.002","article-title":"New Advances in Adaptive Thermogenesis: UCP1 and Beyond","volume":"29","author":"Chouchani","year":"2019","journal-title":"Cell Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e12958","DOI":"10.1111\/obr.12958","article-title":"White adipose tissue mitochondrial metabolism in health and in obesity","volume":"21","author":"Heinonen","year":"2020","journal-title":"Obes. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.cmet.2019.02.011","article-title":"Mitochondria Bound to Lipid Droplets: Where Mitochondrial Dynamics Regulate Lipid Storage and Utilization","volume":"29","author":"Benador","year":"2019","journal-title":"Cell Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.cmet.2018.03.003","article-title":"Mitochondria Bound to Lipid Droplets Have Unique Bioenergetics, Composition, and Dynamics that Support Lipid Droplet Expansion","volume":"27","author":"Benador","year":"2018","journal-title":"Cell Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1096\/fj.201601156R","article-title":"Ceramides and mitochondrial fatty acid oxidation in obesity","volume":"31","author":"Fucho","year":"2017","journal-title":"FASEB J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1042\/bj2410783","article-title":"Chlorpromazine and Carnitine-Dependency of Rat-Liver Peroxisomal Beta-Oxidation of Long-Chain Fatty-Acids","volume":"241","author":"Vamecq","year":"1987","journal-title":"Biochem. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"102190","DOI":"10.1016\/j.coph.2022.102190","article-title":"Adipocyte purinergic receptors activated by uracil nucleotides as obesity and type 2 diabetes targets","volume":"63","author":"Jain","year":"2022","journal-title":"Curr. Opin. Pharm."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"eaaf5375","DOI":"10.1126\/science.aaf5375","article-title":"An adipo-biliary-uridine axis that regulates energy homeostasis","volume":"355","author":"Deng","year":"2017","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"114393","DOI":"10.1016\/j.bcp.2020.114393","article-title":"Purinergic signaling in diabetes and metabolism","volume":"187","author":"Jain","year":"2021","journal-title":"Biochem. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"718429","DOI":"10.3389\/fendo.2021.718429","article-title":"Purinergic Signaling in Liver Pathophysiology","volume":"12","author":"Jain","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molmet.2018.02.013","article-title":"Adipocyte Xbp1s overexpression drives uridine production and reduces obesity","volume":"11","author":"Deng","year":"2018","journal-title":"Mol. Metab."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/11\/2460\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:18:23Z","timestamp":1760145503000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/11\/2460"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,15]]},"references-count":64,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["pharmaceutics14112460"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14112460","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,15]]}}}