{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:54:05Z","timestamp":1791838445626,"version":"4.3.4"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["2022YFD130040307"],"award-info":[{"award-number":["2022YFD130040307"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["KYCXJC2024001"],"award-info":[{"award-number":["KYCXJC2024001"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2022YFD130040307"],"award-info":[{"award-number":["2022YFD130040307"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["KYCXJC2024001"],"award-info":[{"award-number":["KYCXJC2024001"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Iron overload is a common complication in various chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD). Lipid and bile acid metabolism disorders are regarded as crucial hallmarks of NAFLD. However, effects of iron accumulation on lipid and bile acid metabolism are not well understood. Ferulic acid (FA) can chelate iron and regulate lipid and bile acid metabolism, but its potential to alleviate lipid and bile acid metabolism disorders caused by iron overload remains unclear. Here, in vitro experiments, iron overload induced oxidative stress, apoptosis, genomic instability, and lipid deposition in AML12 cells. FA reduced lipid and bile acid synthesis while increasing fatty acid \u03b2-oxidation and bile acid export, as indicated by increased mRNA expression of PPAR\u03b1, Acox1, Adipoq, Bsep, and Shp, and decreased mRNA expression of Fasn, Acc, and Cyp7a1. In vivo experiments, FA mitigated liver injury in mice caused by iron overload, as indicated by reduced AST and ALT activities, and decreased iron levels in both serum and liver. RNA-seq results showed that differentially expressed genes were enriched in biological processes related to lipid metabolism, lipid biosynthesis, lipid storage, and transport. Furthermore, FA decreased cholesterol and bile acid contents, downregulated lipogenesis protein FASN, and bile acid synthesis protein CYP7A1. In conclusion, FA can protect the liver from lipid and bile acid metabolism disorders caused by iron overload by targeting FASN and CYP7A1. Consequently, FA, as a dietary supplement, can potentially prevent and treat chronic liver diseases related to iron overload by regulating lipid and bile acid metabolism.<\/jats:p>","DOI":"10.3390\/antiox13111277","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T04:28:43Z","timestamp":1729657723000},"page":"1277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Ferulic Acid Alleviates Lipid and Bile Acid Metabolism Disorders by Targeting FASN and CYP7A1 in Iron Overload-Treated Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-1392","authenticated-orcid":false,"given":"Yaxu","family":"Liang","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongming","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8409-5534","authenticated-orcid":false,"given":"Zhibo","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weite","family":"Li","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Long","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Ning","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yuan","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8622-8078","authenticated-orcid":false,"given":"Xiang","family":"Zhong","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"},{"name":"Natural Plant and Animal Health Innovation Institute, NJAU-Cohoo Biotechnology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1152\/physrev.00008.2013","article-title":"Systemic iron homeostasis","volume":"93","author":"Ganz","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.12659\/MSM.896494","article-title":"The Role of Iron and Iron Overload in Chronic Liver Disease","volume":"22","author":"Milic","year":"2016","journal-title":"Med Sci. Monit."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/hep4.1190","article-title":"Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease","volume":"2","author":"Britton","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8257","DOI":"10.1021\/acs.jafc.1c02596","article-title":"Gamma-Linolenic Acid Prevents Lipid Metabolism Disorder in Palmitic Acid-Treated Alpha Mouse Liver-12 Cells by Balancing Autophagy and Apoptosis via the LKB1-AMPK-mTOR Pathway","volume":"69","author":"Liang","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.jhep.2013.04.031","article-title":"Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis","volume":"59","author":"Frau","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.bcp.2006.07.004","article-title":"Regulation of inflammation and redox signaling by dietary polyphenols","volume":"72","author":"Rahman","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1159\/000491755","article-title":"Antioxidant Properties of Ferulic Acid and Its Possible Application","volume":"31","author":"Zdunska","year":"2018","journal-title":"Ski. Pharmacol. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Aalikhani, M., Khalili, M., and Jahanshahi, M. (2022). The natural iron chelators\u2019 ferulic acid and caffeic acid rescue mice\u2019s brains from side effects of iron overload. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.951725"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kose, T., Sharp, P.A., and Latunde-Dada, G.O. (2023). Phenolic Acids Rescue Iron-Induced Damage in Murine Pancreatic Cells and Tissues. Molecules, 28.","DOI":"10.3390\/molecules28104084"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20631","DOI":"10.1007\/s11356-019-05420-7","article-title":"Influence of ferulic acid consumption in ameliorating the cadmium-induced liver and renal oxidative damage in rats","volume":"26","author":"Sanjeev","year":"2019","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6446","DOI":"10.3390\/nu7085283","article-title":"Ferulic Acid Alleviates Changes in a Rat Model of Metabolic Syndrome Induced by High-Carbohydrate, High-Fat Diet","volume":"7","author":"Senaphan","year":"2015","journal-title":"Nutrients"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gu, Y., Zhang, Y., Li, M., Huang, Z., Jiang, J., Chen, Y., Chen, J., Jia, Y., Zhang, L., and Zhou, F. (2021). Ferulic Acid Ameliorates Atherosclerotic Injury by Modulating Gut Microbiota and Lipid Metabolism. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.621339"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111978","DOI":"10.1016\/j.fct.2021.111978","article-title":"Ferulic acid ameliorates intrahepatic triglyceride accumulation in vitro but not in high fat diet-fed C57BL\/6 mice","volume":"149","author":"Wang","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"150","DOI":"10.3164\/jcbn.09-98","article-title":"Influence of oryzanol and ferulic Acid on the lipid metabolism and antioxidative status in high fat-fed mice","volume":"46","author":"Son","year":"2010","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/hep.32270","article-title":"Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron-induced hepatotoxicity","volume":"76","author":"Xiong","year":"2022","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.semcancer.2020.10.003","article-title":"Dietary fat, bile acid metabolism and colorectal cancer","volume":"73","author":"Ocvirk","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1152\/physrev.00010.2008","article-title":"Role of bile acids and bile acid receptors in metabolic regulation","volume":"89","author":"Lefebvre","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nm.3760","article-title":"Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance","volume":"21","author":"Fang","year":"2015","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1172\/JCI0215387","article-title":"Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype","volume":"110","author":"Pullinger","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Luo, Z., Li, M., Yang, J., Li, J., Zhang, Y., Liu, F., El-Omar, E., Han, L., Bian, J., and Gong, L. (2022). Ferulic acid attenuates high-fat diet-induced hypercholesterolemia by activating classic bile acid synthesis pathway. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.976638"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1478-3231.2008.01793.x","article-title":"Curcumin reduces the toxic effects of iron loading in rat liver epithelial cells","volume":"29","author":"Messner","year":"2009","journal-title":"Liver Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1111\/acel.12071","article-title":"DNA damage in normally and prematurely aged mice","volume":"12","author":"Maslov","year":"2013","journal-title":"Aging Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/leu.2010.6","article-title":"gammaH2AX: A sensitive molecular marker of DNA damage and repair","volume":"24","author":"Mah","year":"2010","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.molcel.2015.01.034","article-title":"Biology of Poly(ADP-Ribose) Polymerases: The Factotums of Cell Maintenance","volume":"58","author":"Bai","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Srinivas, U.S., Tan, B.W.Q., Vellayappan, B.A., and Jeyasekharan, A.D. (2019). ROS and the DNA damage response in cancer. Redox Biol., 25.","DOI":"10.1016\/j.redox.2018.101084"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1124\/pr.113.008201","article-title":"Bile acid signaling in metabolic disease and drug therapy","volume":"66","author":"Li","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.1038\/modpathol.3800715","article-title":"Iron overload syndromes and the liver","volume":"20","author":"Batts","year":"2007","journal-title":"Mod. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1073\/pnas.91.2.674","article-title":"Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha","volume":"91","author":"Wu","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hsiao, P.J., Chiou, H.C., Jiang, H.J., Lee, M.Y., Hsieh, T.J., and Kuo, K.K. (2017). Pioglitazone Enhances Cytosolic Lipolysis, beta-oxidation and Autophagy to Ameliorate Hepatic Steatosis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-09702-3"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1128\/MCB.00227-16","article-title":"Acetylation of Mitochondrial Trifunctional Protein alpha-Subunit Enhances Its Stability to Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease","volume":"36","author":"Guo","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1097\/HEP.0000000000000279","article-title":"Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease","volume":"78","author":"Gao","year":"2023","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1016\/j.jnutbio.2013.02.004","article-title":"Effects of excess dietary iron and fat on glucose and lipid metabolism","volume":"24","author":"Choi","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.jhep.2011.08.025","article-title":"The interaction of hepatic lipid and glucose metabolism in liver diseases","volume":"56","author":"Bechmann","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Prasnicka, A., Lastuvkova, H., Alaei Faradonbeh, F., Cermanova, J., Hroch, M., Mokry, J., Dolezelova, E., Pavek, P., Zizalova, K., and Vitek, L. (2019). Iron overload reduces synthesis and elimination of bile acids in rat liver. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-46150-7"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/cphy.c120023","article-title":"Bile acid metabolism and signaling","volume":"3","author":"Chiang","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.cbi.2018.06.028","article-title":"Methyl ferulic acid attenuates ethanol-induced hepatic steatosis by regulating AMPK and FoxO1 Pathways in Rats and L-02 cells","volume":"291","author":"Cheng","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lambruschini, C., Demori, I., El Rashed, Z., Rovegno, L., Canessa, E., Cortese, K., Grasselli, E., and Moni, L. (2020). Synthesis, Photoisomerization, Antioxidant Activity, and Lipid-Lowering Effect of Ferulic Acid and Feruloyl Amides. Molecules, 26.","DOI":"10.3390\/molecules26010089"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Fhu, C.W., and Ali, A. (2020). Fatty Acid Synthase: An Emerging Target in Cancer. Molecules, 25.","DOI":"10.3390\/molecules25173935"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Koh, E.J., Kim, K.J., Seo, Y.J., Choi, J., and Lee, B.Y. (2017). Modulation of HO-1 by Ferulic Acid Attenuates Adipocyte Differentiation in 3T3-L1 Cells. Molecules, 22.","DOI":"10.3390\/molecules22050745"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"He, M., Li, X., Yu, L., Deng, S., Gu, N., Li, L., Jia, J., and Li, B. (2022). Double-Sided Nano-ZnO: Superior Antibacterial Properties and Induced Hepatotoxicity in Zebrafish Embryos. Toxics, 10.","DOI":"10.3390\/toxics10030144"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e52280","DOI":"10.15252\/embr.202052280","article-title":"PPARalpha alleviates iron overload-induced ferroptosis in mouse liver","volume":"23","author":"Xing","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.aninu.2021.08.004","article-title":"Ferulic acid mediates prebiotic responses of cereal-derived arabinoxylans on host health","volume":"9","author":"Zhang","year":"2022","journal-title":"Anim. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yu Cai Lim, M., and Kiat Ho, H. (2024). Pharmacological modulation of cholesterol 7alpha-hydroxylase (CYP7A1) as a therapeutic strategy for hypercholesterolemia. Biochem. Pharmacol., 220.","DOI":"10.1016\/j.bcp.2023.115985"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.jhep.2010.10.022","article-title":"Nitric oxide mimics transcriptional and post-translational regulation during alpha-tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes","volume":"55","author":"Gonzalez","year":"2011","journal-title":"J. Hepatol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/11\/1277\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:18:19Z","timestamp":1760113099000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/11\/1277"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,23]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["antiox13111277"],"URL":"https:\/\/doi.org\/10.3390\/antiox13111277","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,23]]}}}