{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:28:35Z","timestamp":1779294515796,"version":"3.51.4"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,19]],"date-time":"2020-01-19T00:00:00Z","timestamp":1579392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE2458\/15 and HE2458\/18"],"award-info":[{"award-number":["HE2458\/15 and HE2458\/18"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cholestasis occurs in different clinical circumstances and leads to severe hepatic disorders. The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein that modulates multiple signal transduction pathways in a tissue- and cell context-specific manner. In this study, we aimed to gain insight into the function of FHL2 in cholestatic liver injury. FHL2 expression was significantly increased in the bile duct ligation (BDL) model in mice. In Fhl2-deficient (Fhl2-ko) mice, BDL caused a more severe portal and parenchymal inflammation, extended portal fibrosis, higher serum transaminase levels, and higher pro-inflammatory and pro-fibrogenic gene expression compared to wild type (wt) mice. FHL2 depletion in HepG2 cells with siRNA resulted in a higher expression of the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) gene. Furthermore, FHL2-depleted HepG2 cells showed higher expression of markers for oxidative stress, lower B-cell lymphoma 2 (Bcl2) expression, and higher Bcl2-associated X protein (BAX) expression after stimulation with deoxycholic acid (DCA). In hepatic stellate cells (HSCs), FHL2 depletion caused an increased expression of TGF-\u03b2 and several pro-fibrogenic matrix metalloproteinases. In summary, our study shows that deficiency in FHL2 aggravates cholestatic liver injury and suggests FHL2-mediated effects on bile acid metabolisms and HSCs as potential mechanisms for pronounced hepatocellular injury and fibrosis.<\/jats:p>","DOI":"10.3390\/cells9010248","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T03:04:43Z","timestamp":1579575883000},"page":"248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Four-And-A-Half LIM-Domain Protein 2 (FHL2) Deficiency Aggravates Cholestatic Liver Injury"],"prefix":"10.3390","volume":"9","author":[{"given":"Judith","family":"Sommer","sequence":"first","affiliation":[{"name":"Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-N\u00fcrnberg, Fahrstr. 17, D-91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2560-9598","authenticated-orcid":false,"given":"Christoph","family":"Dorn","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, University Regensburg, D-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erwin","family":"G\u00e4bele","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, D-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frauke","family":"Bataille","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Regensburg, D-93049 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Freese","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-N\u00fcrnberg, Fahrstr. 17, D-91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatjana","family":"Seitz","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-N\u00fcrnberg, Fahrstr. 17, D-91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang E.","family":"Thasler","sequence":"additional","affiliation":[{"name":"Hepacult GmbH, D-82152 Planegg\/Martinsried, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhard","family":"B\u00fcttner","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Cologne, D-50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0931","authenticated-orcid":false,"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8147-394X","authenticated-orcid":false,"given":"Anja","family":"Bosserhoff","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-N\u00fcrnberg, Fahrstr. 17, D-91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center (CCC) Erlangen-EMN, D-91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus","family":"Hellerbrand","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-N\u00fcrnberg, Fahrstr. 17, D-91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center (CCC) Erlangen-EMN, D-91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri3623","article-title":"Liver fibrosis and repair: Immune regulation of wound healing in a solid organ","volume":"14","author":"Pellicoro","year":"2014","journal-title":"Nat. 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