{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:58:48Z","timestamp":1778637528314,"version":"3.51.4"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":224,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P25599-B19"],"award-info":[{"award-number":["P25599-B19"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["F3517-B20"],"award-info":[{"award-number":["F3517-B20"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P25925-B20"],"award-info":[{"award-number":["P25925-B20"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["SFB-F28"],"award-info":[{"award-number":["SFB-F28"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the GH receptor gene (Ghr<jats:sup>\u2013\/\u2013<\/jats:sup>, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2<jats:sup>\u2013\/\u2013<\/jats:sup>), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr<jats:sup>\u2013\/\u2013<\/jats:sup>;Mdr2<jats:sup>\u2013\/\u2013<\/jats:sup> mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation, and increased collagen deposition relative to Mdr2<jats:sup>\u2013\/\u2013<\/jats:sup> mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr<jats:sup>\u2013\/\u2013<\/jats:sup>;Mdr2<jats:sup>\u2013\/\u2013<\/jats:sup> mice had a pronounced down\u2010regulation of hepatoprotective genes <jats:italic toggle=\"yes\">Hnf6<\/jats:italic>, <jats:italic toggle=\"yes\">Egfr<\/jats:italic>, and <jats:italic toggle=\"yes\">Igf\u20101<\/jats:italic>, and significantly increased levels of reactive oxygen species (ROS) and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr<jats:sup>\u2013\/\u2013<\/jats:sup>) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis, and bile infarcts compared to their wild\u2010type littermates, indicating that loss of <jats:italic toggle=\"yes\">Ghr<\/jats:italic> renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr<jats:sup>\u2013\/\u2013<\/jats:sup>;Mdr2<jats:sup>\u2013\/\u2013<\/jats:sup> mice displayed a significant decrease in tumor incidence compared to Mdr2<jats:sup>\u2013\/\u2013<\/jats:sup> mice, indicating that loss of <jats:italic toggle=\"yes\">Ghr<\/jats:italic> signaling may slow the progression from fibrosis\/cirrhosis to cancer in the liver. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments. (H<jats:sc>epatology<\/jats:sc> 2015;61:613\u2010626)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.27408","type":"journal-article","created":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T15:08:50Z","timestamp":1409584130000},"page":"613-626","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Growth hormone resistance exacerbates cholestasis\u2010induced murine liver fibrosis"],"prefix":"10.1097","volume":"61","author":[{"given":"Patricia","family":"Stiedl","sequence":"first","affiliation":[{"name":"Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"McMahon","sequence":"additional","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leander","family":"Blaas","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition,Karolinska Institute,Huddinge,Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Stanek","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmin","family":"Svinka","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Comprehensive Cancer Center CCC,Institute for Cancer Research, Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrice","family":"Grabner","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gernot","family":"Zollner","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine,Medical University of Graz,Graz,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja M.","family":"Kessler","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medical University of Graz,Graz,Austria"},{"name":"Pharmaceutical Biology, Department of Pharmacy,Saarland University,Saarbr\u00fccken,Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thierry","family":"Claudel","sequence":"additional","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Biomodels Austria, Institute of Animal Breeding and Genetics,University of Veterinary Medicine Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Mikulits","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Comprehensive Cancer Center CCC,Institute for Cancer Research, Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Bilban","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"Esterbauer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Eferl","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Comprehensive Cancer Center CCC,Institute for Cancer Research, Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Haybaeck","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medical University of Graz,Graz,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Trauner","sequence":"additional","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilio","family":"Casanova","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria"},{"name":"Institute of Pharmacology, Center of Physiology and Pharmacology, Comprehensive Cancer Center,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2015,1,20]]},"reference":[{"key":"hep27408-bib-0001-20241017","first-page":"1","article-title":"Molecular basis of hepatic fibrosis","volume":"5","year":"2003","journal-title":"Expert Rev Mol Med"},{"key":"hep27408-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","year":"2005","journal-title":"J Clin Invest"},{"key":"hep27408-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1476-5926-6-7","article-title":"Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options","volume":"6","year":"2007","journal-title":"Comp Hepatol"},{"key":"hep27408-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1749-6632.2011.06100.x","article-title":"Growth hormone\u2010STAT5 regulation of growth, hepatocellular carcinoma, and liver metabolism","volume":"1229","year":"2011","journal-title":"Ann N Y Acad Sci"},{"key":"hep27408-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1111\/j.1478-3231.2010.02428.x","article-title":"Insulin\u2010like growth factor\u2010I and the liver","volume":"31","year":"2011","journal-title":"Liver Int Off J Int Assoc Study Liver"},{"key":"hep27408-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"13215","DOI":"10.1073\/pnas.94.24.13215","article-title":"A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor\/binding protein gene (the Laron mouse)","volume":"94","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep27408-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1053\/j.gastro.2005.10.018","article-title":"24\u2010norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice","volume":"130","year":"2006","journal-title":"Gastroenterology"},{"key":"hep27408-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"17081","DOI":"10.1073\/pnas.0704126104","article-title":"The EGF receptor is required for efficient liver regeneration","volume":"104","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep27408-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1210\/mend.14.2.0423","article-title":"Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF\u20104 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone","volume":"14","year":"2000","journal-title":"Mol Endocrinol"},{"key":"hep27408-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"G357","DOI":"10.1152\/ajpgi.00581.2007","article-title":"Transcriptional activation by growth hormone of HNF\u20106\u2010regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice","volume":"295","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep27408-bib-0011-20241017","first-page":"299","article-title":"GH modulates hepatic epidermal growth factor signaling in the mouse","volume":"204","year":"2010","journal-title":"J Endocrinol"},{"key":"hep27408-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3748\/wjg.15.1677","article-title":"Bile\u2010acid\u2010induced cell injury and protection","volume":"15","year":"2009","journal-title":"World J Gastroenterol"},{"key":"hep27408-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/BF03401914","article-title":"Ursodeoxycholic acid may inhibit deoxycholic acid\u2010induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production","volume":"4","year":"1998","journal-title":"Mol Med"},{"key":"hep27408-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1053\/jhep.2001.22702","article-title":"Bile acid\u2010induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition","volume":"33","year":"2001","journal-title":"Hepatology"},{"key":"hep27408-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1002\/hep.1840400427","article-title":"Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes","volume":"40","year":"2004","journal-title":"Hepatology"},{"key":"hep27408-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3109\/10715769809065818","article-title":"Lipid peroxidation and biogenic aldehydes: from the identification of 4\u2010hydroxynonenal to further achievements in biopathology","volume":"28","year":"1998","journal-title":"Free Radic Res"},{"key":"hep27408-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1080\/01926230701311344","article-title":"Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease","volume":"35","year":"2007","journal-title":"Toxicol Pathol"},{"key":"hep27408-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1042\/BJ20112023","article-title":"The Bcl\u20102 proteins Noxa and Bcl\u2010xL co\u2010ordinately regulate oxidative stress\u2010induced apoptosis","volume":"444","year":"2012","journal-title":"Biochem J"},{"key":"hep27408-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1038\/cdd.2013.52","article-title":"p53 regulates a non\u2010apoptotic death induced by ROS","volume":"20","year":"2013","journal-title":"Cell Death Differ"},{"key":"hep27408-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1101\/gad.13.1.76","article-title":"Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino\u2010terminal Neh2 domain","volume":"13","year":"1999","journal-title":"Genes Dev"},{"key":"hep27408-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/S0168-8278(97)80161-4","article-title":"Insulin\u2010like growth factor\u2010I in liver cirrhosis","volume":"27","year":"1997","journal-title":"J Hepatol"},{"key":"hep27408-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1002\/hep.23469","article-title":"Disruption of the growth hormone\u2010Signal transducer and activator of transcription 5\u2010Insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis","volume":"51","year":"2010","journal-title":"Hepatology"},{"key":"hep27408-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1053\/j.gastro.2010.02.049","article-title":"Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis","volume":"138","year":"2010","journal-title":"Gastroenterology"},{"key":"hep27408-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.2741\/3886","article-title":"JAK\u2010STAT signaling in hepatic fibrosis","volume":"16","year":"2011","journal-title":"Front Biosci Landmark Ed"},{"key":"hep27408-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1053\/gast.1997.v113.pm9352873","article-title":"Hepatoprotective effects of insulin\u2010like growth factor I in rats with carbon tetrachloride\u2010induced cirrhosis","volume":"113","year":"1997","journal-title":"Gastroenterology"},{"key":"hep27408-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.jhep.2005.03.025","article-title":"Insulin\u2010like growth factor I (IGF\u2010I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial","volume":"43","year":"2005","journal-title":"J Hepatol"},{"key":"hep27408-bib-0027-20241017","first-page":"156","article-title":"[Insulin\u2010like growth factor I (IGF\u2010I) and liver cirrhosis]","volume":"99","year":"2007","journal-title":"Rev Esp Enfermedades Dig Organo Of Soc Esp Patol Dig"},{"key":"hep27408-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1053\/j.gastro.2006.12.024","article-title":"Growth hormone reverses nonalcoholic steatohepatitis in a patient with adult growth hormone deficiency","volume":"132","year":"2007","journal-title":"Gastroenterology"},{"key":"hep27408-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/hep.20140","article-title":"Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction","volume":"39","year":"2004","journal-title":"Hepatology"},{"key":"hep27408-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"206","DOI":"10.2741\/3922","article-title":"Genetic determinants of acquired cholestasis: a systems biology approach","volume":"17","year":"2012","journal-title":"Front Biosci Landmark Ed"},{"key":"hep27408-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jhep.2012.08.002","article-title":"Bile acid transporters and regulatory nuclear receptors in the liver and beyond","volume":"58","year":"2013","journal-title":"J Hepatol"},{"key":"hep27408-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1136\/gut.2003.024505","article-title":"Expression of insulin\u2010like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury","volume":"54","year":"2005","journal-title":"Gut"},{"key":"hep27408-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1677\/JOE-08-0269","article-title":"Epithelial injury induces an innate repair mechanism linked to cellular senescence and fibrosis involving IGF\u2010binding protein\u20105","volume":"199","year":"2008","journal-title":"J Endocrinol"},{"key":"hep27408-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1136\/gut.2004.053850","article-title":"Apoptosis: a mechanism of acute and chronic liver injury","volume":"54","year":"2005","journal-title":"Gut"},{"key":"hep27408-bib-0035-20241017","first-page":"1","article-title":"Pathophysiological significance of hepatic apoptosis","volume":"2013","year":"2013","journal-title":"ISRN Hepatol"},{"key":"hep27408-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1210\/en.2010-1193","article-title":"GH receptor plays a major role in liver regeneration through the control of EGFR and ERK1\/2 activation","volume":"152","year":"2011","journal-title":"Endocrinology"},{"key":"hep27408-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.bcp.2005.08.020","article-title":"Inhibition of insulin\/IGF\u20101 receptor signaling enhances bile acid toxicity in primary hepatocytes","volume":"70","year":"2005","journal-title":"Biochem Pharmacol"},{"key":"hep27408-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.jhep.2004.04.007","article-title":"The cirrhotic hepatocyte: navigating between Scylla and Charybdis","volume":"40","year":"2004","journal-title":"J Hepatol"},{"key":"hep27408-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1093\/carcin\/22.11.1853","article-title":"The little mutation suppresses DEN\u2010induced hepatocarcinogenesis in mice and abrogates genetic and hormonal modulation of susceptibility","volume":"22","year":"2001","journal-title":"Carcinogenesis"},{"key":"hep27408-bib-0040-20241017","first-page":"70ra13","article-title":"Growth hormone receptor deficiency is associated with a major reduction in pro\u2010aging signaling, cancer, and diabetes in humans","volume":"3","year":"2011","journal-title":"Sci Transl Med"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27408","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27408","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201502000-00027","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:01:33Z","timestamp":1729209693000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201502000-00027"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,20]]},"references-count":40,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2015]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.27408","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,20]]},"assertion":[{"value":"2014-04-02","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-08-28","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}