{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T17:45:18Z","timestamp":1770140718905,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Society of Surgical Research","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"New National Excellence Program of the Ministry of Human Capacities of Hungary","award":["\u00daNKP-20-3-I-SE-9; ND"],"award-info":[{"award-number":["\u00daNKP-20-3-I-SE-9; ND"]}]},{"name":"Semmelweis University 250+ PhD Excellence Grant","award":["EFOP-3.6.3-VEKOP-16-2017 00009"],"award-info":[{"award-number":["EFOP-3.6.3-VEKOP-16-2017 00009"]}]},{"name":"Bolyai J\u00e1nos Research Grant of the Hungarian Academy of Sciences","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"Dutch Cancer Foundation","award":["KWF project # 10666"],"award-info":[{"award-number":["KWF project # 10666"]}]},{"name":"Zhejiang Provincial Foreign Expert Program Grant, Zhejiang Provincial Key Natural Science Foundation of China","award":["#Z20H160031"],"award-info":[{"award-number":["#Z20H160031"]}]},{"name":"grant for the establishment of the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Background: the role of bile acid (BA)-induced farnesoid X receptor (Fxr) signaling in liver regeneration following associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was investigated in a rat model. Methods: Male Wistar rats underwent portal vein ligation (PVL) (n = 30) or ALPPS (n = 30). Animals were sacrificed pre-operatively and at 24, 48, 72, or 168 h after intervention. Regeneration rate, Ki67 index, hemodynamic changes in the hepatic circulation, and BA levels were assessed. Transcriptome analysis of molecular regulators involved in the Fxr signaling pathway, BA transport, and BA production was performed. Results: ALLPS induced more extensive liver regeneration (p &lt; 0.001) and elevation of systemic and portal BA levels (p &lt; 0.05) than PVL. The mRNA levels of proteins participating in hepatic Fxr signaling were comparable between the intervention groups. More profound activation of the intestinal Fxr pathway was observed 24 h after ALPPS compared to PVL. Conclusion: Our study elaborates on a possible linkage between BA-induced Fxr signaling and accelerated liver regeneration induced by ALPPS in rats. ALPPS could trigger liver regeneration via intestinal Fxr signaling cascades instead of hepatic Fxr signaling, thereby deviating from the mechanism of BA-mediated regeneration following one-stage hepatectomy.<\/jats:p>","DOI":"10.3390\/curroncol28060438","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T21:52:32Z","timestamp":1639086752000},"page":"5240-5254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Role of Farnesoid X Receptor in Accelerated Liver Regeneration in Rats Subjected to ALPPS"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6918-7406","authenticated-orcid":false,"given":"Noemi","family":"Daradics","sequence":"first","affiliation":[{"name":"Hepato-Pancreatico-Biliary (HPB) Surgical Research Center Hungary, Department of Surgery, Transplantation and Interventional Gastroenterology, Semmelweis University, 1082 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pim B.","family":"Olthof","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center, Department of Surgery, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andras","family":"Budai","sequence":"additional","affiliation":[{"name":"2nd Department of Pathology, Semmelweis University, 1091 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-4465","authenticated-orcid":false,"given":"Michal","family":"Heger","sequence":"additional","affiliation":[{"name":"Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314001, China"},{"name":"Laboratory of Experimental Oncology, Department of Pathology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas M.","family":"van Gulik","sequence":"additional","affiliation":[{"name":"Department of Surgery, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andras","family":"Fulop","sequence":"additional","affiliation":[{"name":"Hepato-Pancreatico-Biliary (HPB) Surgical Research Center Hungary, Department of Surgery, Transplantation and Interventional Gastroenterology, Semmelweis University, 1082 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attila","family":"Szijarto","sequence":"additional","affiliation":[{"name":"Hepato-Pancreatico-Biliary (HPB) Surgical Research Center Hungary, Department of Surgery, Transplantation and Interventional Gastroenterology, Semmelweis University, 1082 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.amjsurg.2008.04.022","article-title":"Present status and future perspectives of preoperative portal vein embolization","volume":"197","author":"Liu","year":"2009","journal-title":"Am. J. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1159\/000335713","article-title":"How much remnant is enough in liver resection?","volume":"29","author":"Guglielmi","year":"2012","journal-title":"Dig. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s00423-017-1591-8","article-title":"Portal vein embolization in extended liver resection","volume":"402","author":"Narula","year":"2017","journal-title":"Langenbeck\u2019s Arch. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1002\/bjs.10290","article-title":"Meta-analysis of associating liver partition with portal vein ligation and portal vein occlusion for two-stage hepatectomy","volume":"103","author":"Eshmuminov","year":"2016","journal-title":"Br. J. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1097\/SLA.0b013e31824856f5","article-title":"Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings","volume":"255","author":"Schnitzbauer","year":"2012","journal-title":"Ann. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.5582\/bst.2015.01131","article-title":"Associating liver partition and portal vein ligation (ALPPS): Taking a view of trails","volume":"9","author":"Takamoto","year":"2015","journal-title":"Biosci. Trends."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s13304-016-0401-0","article-title":"A literature review of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): So far, so good","volume":"69","author":"Boccalatte","year":"2017","journal-title":"Updates Surg."},{"key":"ref_8","first-page":"1","article-title":"Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis","volume":"4","author":"Warps","year":"2018","journal-title":"J. Clin. Transl. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1126\/science.1121435","article-title":"Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration","volume":"312","author":"Huang","year":"2006","journal-title":"Science"},{"key":"ref_10","unstructured":"Geier, A., and Trautwein, C. (2021, June 24). Bile Acids Are \u201cHomeotrophic\u201d Sensors of the Functional Hepatic Capacity and Regulate Adaptive Growth during Liver Regeneration. Available online: https:\/\/aasldpubs.onlinelibrary.wiley.com\/doi\/abs\/10.1002\/hep.21521."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1136\/gutjnl-2012-302945","article-title":"Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice","volume":"62","author":"Uriarte","year":"2013","journal-title":"Gut"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1002\/hep.26463","article-title":"The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice","volume":"58","author":"Doignon","year":"2013","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1002\/hep.25918","article-title":"Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice","volume":"56","author":"Borude","year":"2012","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1002\/hep.25905","article-title":"Promotion of liver regeneration\/repair by farnesoid X receptor in both liver and intestine in mice","volume":"56","author":"Zhang","year":"2012","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"G893","DOI":"10.1152\/ajpgi.00337.2013","article-title":"Fibroblast growth factor 15 deficiency impairs liver regeneration in mice","volume":"306","author":"Kong","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/bjs.10466","article-title":"Effect of obeticholic acid on liver regeneration following portal vein embolization in an experimental model","volume":"104","author":"Olthof","year":"2017","journal-title":"Br. J. Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16529","DOI":"10.1038\/s41598-018-33070-1","article-title":"FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis","volume":"8","author":"Olthof","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1038\/srep08455","article-title":"Simultaneous bile duct and portal vein ligation induces faster atrophy\/hypertrophy complex than portal vein ligation: Role of bile acids","volume":"5","author":"Ren","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kilkenny, C., Browne, W.J., Cuthill, I.C., Emerson, M., and Altman, D.G. (2010). Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000412"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1159\/000453108","article-title":"Animal Models for Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS): Achievements and Future Perspectives","volume":"58","author":"Budai","year":"2017","journal-title":"Eur. Surg. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Naugler, W.E. (2014). Bile acid flux is necessary for normal liver regeneration. PLoS ONE., 9.","DOI":"10.1371\/journal.pone.0097426"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"de Haan, L.R., Verheij, J., van Golen, R.F., Horneffer-van der Sluis, V., Lewis, M.R., Beuers, U.H.W., van Gulik, T.M., Olde Damink, S.W.M., Schaap, F.G., and Heger, M. (2021). Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid. Biomolecules, 11.","DOI":"10.3390\/biom11020260"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/bjs5.18","article-title":"Experimental evaluation of liver regeneration patterns and liver function following ALPPS","volume":"1","author":"Shi","year":"2017","journal-title":"BJS Open"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"37","DOI":"10.21037\/tgh.2019.12.01","article-title":"Associated liver partition and portal vein ligation for staged hepatectomy: A review","volume":"5","author":"Chan","year":"2020","journal-title":"Transl. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"694","DOI":"10.21037\/hbsn.2019.08.03","article-title":"The role of associating liver partition and portal vein ligation for staged hepatectomy in the management of patients with colorectal liver metastasis","volume":"9","author":"Glinka","year":"2020","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/j.surg.2017.01.005","article-title":"Rapid liver volume increase induced by associating liver partition with portal vein ligation for staged hepatectomy (ALPPS): Is it edema, steatosis, or true proliferation?","volume":"161","author":"Eshmuminov","year":"2017","journal-title":"Surgery"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1159\/000368961","article-title":"Triggered liver regeneration: From experimental model to clinical implications","volume":"54","year":"2015","journal-title":"Eur. Surg. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1097\/SLA.0b013e318248577d","article-title":"Playing Play-Doh to prevent postoperative liver failure: The \u201cALPPS\u201d approach","volume":"255","author":"Clavien","year":"2012","journal-title":"Ann. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.jhep.2008.01.034","article-title":"Liver regeneration and recanalization time course following reversible portal vein embolization","volume":"49","author":"Lainas","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1006\/niox.2001.0373","article-title":"Shear stress-induced nitric oxide release triggers the liver regeneration cascade","volume":"5","author":"Schoen","year":"2001","journal-title":"Nitric Oxide Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1007\/s11605-012-2092-2","article-title":"Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS): Tips and Tricks","volume":"17","author":"Alvarez","year":"2013","journal-title":"J. Gastrointest. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5897","DOI":"10.3748\/wjg.v25.i39.5897","article-title":"Gut-liver axis signaling in portal hypertension","volume":"25","author":"Simbrunner","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.jhep.2019.06.017","article-title":"FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis","volume":"71","author":"Sorribas","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/S0168-8278(01)00296-3","article-title":"Changes in the pool of bile acids in hepatocyte nuclei during rat liver regeneration","volume":"36","author":"Monte","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.jhep.2010.07.012","article-title":"Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis","volume":"54","author":"Doignon","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1245\/s10434-017-5922-3","article-title":"Immaturity of Bile Canalicular\u2013Ductule Networks in the Future Liver Remnant While Associating Liver Partition and Portal Vein Occlusion for Staged Hepatectomy (ALPPS)","volume":"24","author":"Matsuo","year":"2017","journal-title":"Ann. Surg. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jss.2010.06.038","article-title":"Quantitative assessment of liver function after ischemia-reperfusion injury and partial hepatectomy in rats","volume":"172","author":"Heger","year":"2012","journal-title":"J. Surg. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"294","DOI":"10.2967\/jnumed.110.078360","article-title":"Quantitative assessment of hepatic function during liver regeneration in a standardized rat model","volume":"52","author":"Bennink","year":"2011","journal-title":"J. Nucl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.surg.2017.05.022","article-title":"Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: Liver volume overestimates liver function","volume":"162","author":"Olthof","year":"2017","journal-title":"Surgery"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1124\/dmd.30.8.918","article-title":"Role of constitutive androstane receptor in the in vivo induction of Mrp3 and CYP2B1\/2 by phenobarbital","volume":"30","author":"Xiong","year":"2002","journal-title":"Drug. Metab. Dispos."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/S0016-5085(03)01068-0","article-title":"Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice","volume":"125","author":"Wagner","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1136\/gutjnl-2014-307874","article-title":"Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice","volume":"64","author":"Bachofner","year":"2015","journal-title":"Gut"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Otsuka, N., Yoshioka, M., Abe, Y., Nakagawa, Y., Uchinami, H., and Yamamoto, Y. (2020). Reg3\u03b1 and Reg3\u03b2 Expressions Followed by JAK2\/STAT3 Activation Play a Pivotal Role in the Acceleration of Liver Hypertrophy in a Rat ALPPS Model. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114077"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"17567","DOI":"10.1038\/srep17567","article-title":"A preliminary study of ALPPS procedure in a rat model","volume":"5","author":"Shi","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1067\/msy.2002.123008","article-title":"Lack of intestinal bile results in delayed liver regeneration of normal rat liver after hepatectomy accompanied by impaired cyclin E-associated kinase activity","volume":"131","author":"Ueda","year":"2002","journal-title":"Surgery"}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/28\/6\/438\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:43:49Z","timestamp":1760168629000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/28\/6\/438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,9]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["curroncol28060438"],"URL":"https:\/\/doi.org\/10.3390\/curroncol28060438","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,9]]}}}