{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T11:39:28Z","timestamp":1768736368836,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["32001676"],"award-info":[{"award-number":["32001676"]}]},{"name":"National Natural Science Foundation of China","award":["B18053"],"award-info":[{"award-number":["B18053"]}]},{"name":"111 Project from the Education Ministry of China","award":["32001676"],"award-info":[{"award-number":["32001676"]}]},{"name":"111 Project from the Education Ministry of China","award":["B18053"],"award-info":[{"award-number":["B18053"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Increasing hepcidin expression is a vital factor in iron homeostasis imbalance among patients with chronic kidney disease (CKD). Recent studies have elucidated that abnormal serum steroid levels might cause the elevation of hepcidin. Glycochenodeoxycholate (GCDCA), a steroid, is significantly elevated in patients with CKD. However, the correlation between GCDCA and hepcidin has not been elucidated. Decreased serum iron levels and increased hepcidin levels were both detected in patients with CKD in this study. Additionally, the concentrations of GCDCA in nephropathy patients were found to be higher than those in healthy subjects. HepG2 cells were used to investigate the effect of GCDCA on hepcidin in vitro. The results showed that hepcidin expression increased by nearly two-fold against control under 200 \u03bcM GCDCA treatment. The phosphorylation of SMAD1\/5\/8 increased remarkably, while STAT3 and CREBH remained unchanged. GCDCA triggered the expression of farnesoid X receptor (FXR), followed with the transcription and expression of both BMP6 and ALK3 (upward regulators of SMAD1\/5\/8). Thus, GCDCA is a potential regulator for hepcidin, which possibly acts by triggering FXR and the BMP6\/ALK3-SMAD signaling pathway. Furthermore, 40 C57\/BL6 mice were treated with 100 mg\/kg\/d, 200 mg\/kg\/d, and 300 mg\/kg\/d GCDCA to investigate its effect on hepcidin in vivo. The serum level of hepcidin increased in mice treated with 200 mg\/kg\/d and 300 mg\/kg\/d GCDCA, while hemoglobin and serum iron levels decreased. Similarly, the FXR-mediated SMAD signaling pathway was also responsible for activating hepcidin in liver. Overall, it was concluded that GCDCA could induce the expression of hepcidin and reduce serum iron level, in which FXR activation-related SMAD signaling was the main target for GCDCA. Thus, abnormal GCDCA level indicates a potential risk of iron homeostasis imbalance.<\/jats:p>","DOI":"10.3390\/nu14153176","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T00:15:26Z","timestamp":1659485726000},"page":"3176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Glycochenodeoxycholate Affects Iron Homeostasis via Up-Regulating Hepcidin Expression"],"prefix":"10.3390","volume":"14","author":[{"given":"Long-jiao","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Functional Dairy, Co-Constructed by Ministry of Education and Beijing Municipality, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-ping","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Food and Health, Beijing Technology and Business University, Beijing 100048, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi-fan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional Dairy, Co-Constructed by Ministry of Education and Beijing Municipality, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-xue","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional Dairy, Co-Constructed by Ministry of Education and Beijing Municipality, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-li","family":"Qiu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional Dairy, Co-Constructed by Ministry of Education and Beijing Municipality, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional Dairy, Co-Constructed by Ministry of Education and Beijing Municipality, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fa-zheng","family":"Ren","sequence":"additional","affiliation":[{"name":"Key Laboratory of Functional Dairy, Co-Constructed by Ministry of Education and Beijing Municipality, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China"},{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/00062752-200503000-00001","article-title":"Anemia of inflammation: The hepcidin link","volume":"12","author":"Roy","year":"2005","journal-title":"Curr. Opin. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1182\/blood-2002-10-3235","article-title":"Hepcidin, a putative mediator of anemia of in-flammation, is a type II acute-phase protein","volume":"101","author":"Nemeth","year":"2003","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1159\/000098522","article-title":"Hepcidin in anemia and inflammation in chronic kidney disease","volume":"30","author":"Malyszko","year":"2007","journal-title":"Kidney Blood Press. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1001\/jama.2010.890","article-title":"Anemia management and mortality risk in incident hemodialysis patients","volume":"304","author":"Auerbach","year":"2010","journal-title":"J. Am. Med. Assoc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1136\/gutjnl-2019-319766","article-title":"Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents","volume":"69","author":"Wang","year":"2020","journal-title":"Gut"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.redox.2016.09.014","article-title":"Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression","volume":"10","author":"Chen","year":"2016","journal-title":"Redox Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/labinvest.2009.82","article-title":"Cholestasis downregulate hepcidin expression through inhibiting IL-6-induced phosphorylation of signal transducer and activator of transcription 3 signaling","volume":"89","author":"Huang","year":"2009","journal-title":"Lab. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.fsi.2019.06.047","article-title":"Supplementation exogenous bile acid improved growth and intestinal immune function associated with NF-kappa B and TOR signalling pathways in on-growing grass carp (Ctenopharyngodon idella): Enhancement the effect of protein-sparing by dietary lipid","volume":"92","author":"Peng","year":"2019","journal-title":"Fish Shellfish Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"873.11","DOI":"10.1096\/fasebj.2018.32.1_supplement.873.11","article-title":"Evaluation of preparation techniques for optimal hepcidin detection in human hepatocyte culture","volume":"32","author":"Morehouse","year":"2018","journal-title":"FASEB J."},{"key":"ref_10","first-page":"180","article-title":"Hepcidin- A potential novel biomarker for iron status and erythropoietin resistance in pediatric chronic kidney disease","volume":"57","author":"Zaritsky","year":"2009","journal-title":"J. Investig. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.2215\/CJN.02190309","article-title":"Hepcidin for Clinicians","volume":"4","author":"Young","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.ymthe.2019.01.003","article-title":"Oral gavage of ginger nanoparticle-derived lipid vectors carrying Dmt1 siRNA blunts iron loading in murine hereditary hemo-chromatosis","volume":"27","author":"Wang","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4103\/1319-2442.148716","article-title":"Serum hepcidin levels in patients with end-stage renal disease on hemodialysis","volume":"26","author":"Rubab","year":"2015","journal-title":"Saudi J. Kidney Dis. Transplant."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s11255-018-2062-z","article-title":"Impact of serum hepcidin and inflammatory markers on resistance to erythropoiesis-stimulating therapy in haemodialysis patients","volume":"51","author":"Farweez","year":"2019","journal-title":"Int. Urol. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/1744-9987.12837","article-title":"Association of hepcidin with anemia parameters in incident dialysis patients: Differences between dialysis modalities","volume":"24","author":"Lim","year":"2020","journal-title":"Ther. Apher. Dial."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1172\/JCI83831","article-title":"Progesterone receptor membrane component-1 regulates hepcidin biosynthesis","volume":"126","author":"Li","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1002\/ajh.20657","article-title":"Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis","volume":"81","author":"Malyszko","year":"2006","journal-title":"Am. J. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.transproceed.2013.06.020","article-title":"Serum hepcidin level correlates with hyperlipidemia status in patients following allograft renal transplantation","volume":"46","author":"Xue","year":"2014","journal-title":"Transplant. Proc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1182\/blood-2018-99-115234","article-title":"Hepcidin predicts decrease in erythroid expansion in sickle cell disease patients treated with inhaled steroids","volume":"132","author":"Martinez","year":"2018","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ikeda, Y., Tajima, S., Izawa-Ishizawa, Y., Kihira, Y., Ishizawa, K., Tomita, S., Tsuchiya, K., and Tamaki, T. (2012). Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040465"},{"key":"ref_21","first-page":"71","article-title":"Hepcidin and the BMP-SMAD pathway: An unexpected liaison","volume":"Volume 110","author":"Litwack","year":"2019","journal-title":"Iron Metabolism: Hepcidin"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2016.12.034","article-title":"A red carpet for iron metabolism","volume":"168","author":"Muckenthaler","year":"2017","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1126\/science.1176639","article-title":"ER stress controls iron metabolism through induction of hepcidin","volume":"325","author":"Vecchi","year":"2009","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/s00774-008-0850-8","article-title":"Cyclic AMP enhances smad-mediated BMP signaling through PKA-CREB pathway","volume":"26","author":"Ohta","year":"2008","journal-title":"J. Bone Miner. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cmet.2005.10.010","article-title":"A role of SMAD4 in iron metabolism through the positive regulation of hepicidin expression","volume":"2","author":"Wang","year":"2005","journal-title":"Cell Metab."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wu, X., Yung, L.-M., Cheng, W.-H., Yu, P.B., Babitt, J.L., Lin, H.Y., and Xia, Y. (2012). Hepcidin regulation by BMP signaling in macrophages is lipopolysaccharide dependent. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044622"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/ng.335","article-title":"BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism","volume":"41","author":"Andriopoulos","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/MNH.0000000000000374","article-title":"Bile acid receptors and the kidney","volume":"27","author":"Weinstein","year":"2018","journal-title":"Curr. Opin. Nephrol. Hyperten."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"632864","DOI":"10.3389\/fimmu.2021.632864","article-title":"Bile acids elevated in chronic periaortitis could activate far-nesoid-X-receptor to suppress IL-6 production by macrophages","volume":"12","author":"Cao","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_30","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_31","doi-asserted-by":"crossref","first-page":"9435","DOI":"10.1074\/jbc.M209706200","article-title":"A G protein-coupled receptor responsive to bile acids","volume":"278","author":"Kawamata","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_32","first-page":"A665","article-title":"FXR modulates renal lipid metabolism and fibrosis in diabetic nephropathy","volume":"21","author":"Wang","year":"2007","journal-title":"Faseb J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1681\/ASN.2011111078","article-title":"Mechanisms of anemia in CKD","volume":"23","author":"Babitt","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7806","DOI":"10.1074\/jbc.M008922200","article-title":"Hepcidin, a urinary antimicrobial peptide synthesized in the liver","volume":"276","author":"Park","year":"2001","journal-title":"J. Biol. Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/15\/3176\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:01:14Z","timestamp":1760140874000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/15\/3176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,2]]},"references-count":34,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["nu14153176"],"URL":"https:\/\/doi.org\/10.3390\/nu14153176","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,2]]}}}