{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:55:49Z","timestamp":1792007749221,"version":"4.4.0"},"reference-count":51,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T00:00:00Z","timestamp":1717632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Program of Guangzhou","award":["202103000089"],"award-info":[{"award-number":["202103000089"]}]},{"name":"Science and Technology Program of Guangzhou","award":["2020B1515020026"],"award-info":[{"award-number":["2020B1515020026"]}]},{"name":"Guangdong Demonstration Base for Joint Cultivation of Postgraduates","award":["202103000089"],"award-info":[{"award-number":["202103000089"]}]},{"name":"Guangdong Demonstration Base for Joint Cultivation of Postgraduates","award":["2020B1515020026"],"award-info":[{"award-number":["2020B1515020026"]}]},{"name":"Science Foundation for Distinguished Young Scholars of Guangdong, China","award":["202103000089"],"award-info":[{"award-number":["202103000089"]}]},{"name":"Science Foundation for Distinguished Young Scholars of Guangdong, China","award":["2020B1515020026"],"award-info":[{"award-number":["2020B1515020026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world, which begins with liver lipid accumulation and is associated with metabolic syndrome. Also, the name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). We performed focused drug screening and found that Cilostazol effectively ameliorated hepatic steatosis and might offer potential for NAFLD treatment. Our aim was to investigate the therapeutic effects of Cilostazol on the glycolipid metabolism and intestinal flora in NAFLD mice and explore the specific mechanism. In this study, 7-week-old male C57BL\/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD, and then treated with intragastric administration for 12 weeks. The results showed that Cilostazol inhibited liver lipid de novo synthesis by regulating the AMPK-ACC1\/SCD1 pathway and inhibited liver gluconeogenesis by the AMPK-PGC1\u03b1-G6P\/PEPCK pathway. Cilostazol improved the intestinal flora diversity and intestinal microbial composition in the NAFLD mice, and specifically regulated Desulfovibrio and Akkermansia. In addition, Cilostazol increased the level of short-chain fatty acids in the NAFLD mice to a level similar to that in the blank Control group. Cilostazol reduces liver lipid accumulation in NAFLD mice by improving glucose and lipid metabolism disorders and intestinal dysfunction, thereby achieving the purpose of treating NAFLD.<\/jats:p>","DOI":"10.3390\/ijms25116280","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T12:04:28Z","timestamp":1717675468000},"page":"6280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cilostazol Attenuates Hepatic Steatosis and Intestinal Disorders in Nonalcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Tianqi","family":"Min","sequence":"first","affiliation":[{"name":"Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuting","family":"Qiu","sequence":"additional","affiliation":[{"name":"Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Guo","sequence":"additional","affiliation":[{"name":"Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6324-6620","authenticated-orcid":false,"given":"Zhengquan","family":"Su","sequence":"additional","affiliation":[{"name":"Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jhep.2023.01.026","article-title":"Healthcare and socioeconomic costs of NAFLD: A global framework to navigate the uncertainties","volume":"79","author":"Allen","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.7150\/ijbs.27173","article-title":"The PI3K\/AKT pathway in obesity and type 2 diabetes","volume":"14","author":"Huang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1097\/HEP.0000000000000520","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"78","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/hep.32534","article-title":"Relationship between NAFLD and coronary artery disease: A Mendelian randomization study","volume":"77","author":"Ren","year":"2023","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1002\/hep.31845","article-title":"Cancer Risk in Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease: A Populatio-Based Cohort Study","volume":"74","author":"Simon","year":"2021","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1053\/j.gastro.2016.03.005","article-title":"Contribution of Alcoholic and Nonalcoholic Fatty Liver Disease to the Burden of Liver-Related Morbidity and Mortality","volume":"150","author":"Younossi","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1002\/hep.28785","article-title":"The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3389\/fphys.2018.00193","article-title":"The Biological Clock: A Pivotal Hub in Non-alcoholic Fatty Liver Disease Pathogenesis","volume":"9","author":"Mazzoccoli","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1172\/JCI77812","article-title":"The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux","volume":"126","author":"Samuel","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.cmet.2017.08.002","article-title":"Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases","volume":"27","author":"Samuel","year":"2018","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.chom.2017.11.004","article-title":"Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration","volume":"23","author":"Schroeder","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.cmet.2015.03.001","article-title":"Regulation of Obesity-Related Insulin Resistance with Gut Anti-inflammatory Agents","volume":"21","author":"Luck","year":"2015","journal-title":"Cell Metabolism"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.jhep.2019.10.003","article-title":"The gut-liver axis in liver disease: Pathophysiological basis for therapy","volume":"72","author":"Albillos","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1053\/j.gastro.2016.06.022","article-title":"Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol","volume":"151","author":"Rahman","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/jgh.13058","article-title":"Small intestinal bacterial overgrowth and toll-like receptor signaling in patients with non-alcoholic fatty liver disease","volume":"31","author":"Kapil","year":"2016","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/hep.28356","article-title":"The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota","volume":"63","author":"Boursier","year":"2016","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Tang, R., and Li, L. (2021). Modulation of Short-Chain Fatty Acids as Potential Therapy Method for Type 2 Diabetes Mellitus. Can. J. Infect. Dis. Med. Microbiol., 2021.","DOI":"10.1155\/2021\/6632266"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.2337\/db14-1213","article-title":"Short-Chain Fatty Acids Protect Against High-Fat Diet\u2013Induced Obesity via a PPAR\u03b3-Dependent Switch From Lipogenesis to Fat Oxidation","volume":"64","author":"Bleeker","year":"2015","journal-title":"Diabetes"},{"key":"ref_20","first-page":"CD003748","article-title":"Cilostazol for intermittent claudication","volume":"6","author":"Brown","year":"2021","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1016\/j.metabol.2015.07.014","article-title":"Increased expression of ATP-binding cassette transporter A1 (ABCA1) as a possible mechanism for the protective effect of cilostazol against hepatic steatosis","volume":"64","author":"Jeon","year":"2015","journal-title":"Metabolism"},{"key":"ref_22","first-page":"387","article-title":"Advancing Secondary Stroke Prevention Strategies","volume":"98","author":"Madsen","year":"2022","journal-title":"Optim. Timing Dual Antiplatelet Ther. Cilostazol"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e635","DOI":"10.1161\/STROKEAHA.121.035002","article-title":"Cilostazol for Secondary Stroke Prevention","volume":"52","author":"Havenon","year":"2021","journal-title":"Stroke"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1038\/emm.2013.143","article-title":"Cilostazol inhibits insulin-stimulated expression of sterol regulatory binding protein-1c via inhibition of LXR and Sp1","volume":"46","author":"Jung","year":"2014","journal-title":"Exp. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1124\/mol.118.113217","article-title":"Cilostazol Improves HFD-Induced Hepatic Steatosis by Upregulating Hepatic STAMP2 Expression through AMPK","volume":"94","author":"Oh","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gonzato, C., \u017bo\u0142ek, T., Maciejewska, D., Kutner, A., Merlier, F., Haupt, K., Sharma, P.S., Noworyta, K.R., and Kutner, W. (2021). Molecularly imprinted polymer nanoparticles-based electrochemical chemosensors for selective determination of cilostazol and its pharmacologically active primary metabolite in human plasma. Biosens. Bioelectron., 193.","DOI":"10.1016\/j.bios.2021.113542"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.jhep.2016.05.013","article-title":"Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis","volume":"65","author":"Targher","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/dom.14569","article-title":"Weight loss interventions and nonalcoholic fatty liver disease: Optimizing liver outcomes","volume":"24","author":"Finer","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.jhep.2021.11.009","article-title":"A new perspective on NAFLD: Focusing on lipid droplets","volume":"76","author":"Scorletti","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"von Loeffelholz, C., Coldewey, S.M., and Birkenfeld, A.L. (2021). A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies. Cells, 10.","DOI":"10.3390\/cells10071822"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"154589","DOI":"10.1016\/j.phymed.2022.154589","article-title":"Phytochemical gallic acid alleviates nonalcoholic fatty liver disease via AMPK-ACC-PPARa axis through dual regulation of lipid metabolism and mitochondrial function","volume":"109","author":"Zhang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"970292","DOI":"10.3389\/fphys.2022.970292","article-title":"The AMPK pathway in fatty liver disease","volume":"13","author":"Fang","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nassir, F. (2022). NAFLD: Mechanisms, Treatments, and Biomarkers. Biomolecules, 12.","DOI":"10.3390\/biom12060824"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nature01667","article-title":"Insulin-regulated hepatic gluconeogenesis through FOXO1\u2013PGC-1\u03b1 interaction","volume":"423","author":"Puigserver","year":"2003","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.freeradbiomed.2021.03.029","article-title":"Compartmentally scavenging hepatic oxidants through AMPK\/SIRT3-PGC1\u03b1 axis improves mitochondrial biogenesis and glucose catabolism","volume":"168","author":"Wu","year":"2021","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1053\/j.gastro.2020.04.077","article-title":"Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders","volume":"159","author":"Chopyk","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yu, D., Feng, J., You, H., Zhou, S., Bai, Y., He, J., Cao, H., Che, Q., Guo, J., and Su, Z. (2022). The Microstructure, Antibacterial and Antitumor Activities of Chitosan Oligosaccharides and Derivatives. Mar. Drugs, 20.","DOI":"10.3390\/md20010069"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"818","DOI":"10.7150\/ijbs.56214","article-title":"Understanding the Effects of Gut Microbiota Dysbiosis on Nonalcoholic Fatty Liver Disease and the Possible Probiotics Role: Recent Updates","volume":"17","author":"Khan","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1136\/gutjnl-2013-306541","article-title":"Exercise and associated dietary extremes impact on gut microbial diversity","volume":"63","author":"Clarke","year":"2014","journal-title":"Gut"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, L., Liao, Y., Yang, R., Zhu, Z., Zhang, L., Wu, Z., and Sun, X. (2021). An engineered probiotic secreting Sj16 ameliorates colitis via Ruminococcaceae\/butyrate\/retinoic acid axis. Bioeng. Transl. Med., 6.","DOI":"10.1002\/btm2.10219"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-021-02201-4","article-title":"Prevotellaceae produces butyrate to alleviate PD-1\/PD-L1 inhibitor-related cardiotoxicity via PPARalpha-CYP4X1 axis in colonic macrophages","volume":"41","author":"Chen","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1136\/gutjnl-2019-320135","article-title":"Angiogenin maintains gut microbe homeostasis by balancing \u03b1-Proteobacteria and Lachnospiraceae","volume":"70","author":"Sun","year":"2021","journal-title":"Gut"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kaakoush, N.O. (2015). Insights into the Role of Erysipelotrichaceae in the Human Host. Front. Cell. Infect. Microbiol., 5.","DOI":"10.3389\/fcimb.2015.00084"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jnutbio.2016.05.015","article-title":"Colonic inflammation accompanies an increase of \u03b2-catenin signaling and Lachnospiraceae\/Streptococcaceae bacteria in the hind gut of high-fat diet-fed mice","volume":"35","author":"Zeng","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s41564-022-01121-z","article-title":"Identification of shared and disease-specific host gene\u2013microbiome associations across human diseases using multi-omic integration","volume":"7","author":"Priya","year":"2022","journal-title":"Nat. Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.tibtech.2015.06.011","article-title":"Proteobacteria: Microbial signature of dysbiosis in gut microbiota","volume":"33","author":"Shin","year":"2015","journal-title":"Trends Biotechnol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1136\/gutjnl-2019-319664","article-title":"Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites","volume":"70","author":"Zhang","year":"2021","journal-title":"Gut"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.febslet.2014.11.042","article-title":"Desulfovibrio desulfuricans isolates from the gut of a single individual: Structural and biological lipid A characterization","volume":"589","author":"Augusto","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41575-018-0011-z","article-title":"The gut\u2013liver axis and the intersection with the microbiome","volume":"15","author":"Tripathi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4432","DOI":"10.1007\/s12035-016-0004-2","article-title":"The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease","volume":"54","author":"Morris","year":"2017","journal-title":"Mol. Neurobiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6280\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:54:55Z","timestamp":1760108095000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6280"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,6]]},"references-count":51,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25116280"],"URL":"https:\/\/doi.org\/10.3390\/ijms25116280","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,6]]}}}