Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis

dc.contributor.authorHohenester, Simon
dc.contributor.authorKanitz, Veronika
dc.contributor.authorKremer, Andreas E.
dc.contributor.authorPaulusma, Coen C.
dc.contributor.authorWimmer, Ralf
dc.contributor.authorKuehn, Helen
dc.contributor.authorDenk, Gerald
dc.contributor.authorHorst, David
dc.contributor.authorOude Elferink, Ronald
dc.contributor.authorBeuers, Ulrich
dc.date.accessioned2020-03-11
dc.date.available2023-10-09T15:23:37Z
dc.date.created2020
dc.date.issued2020-03-11
dc.description.abstractHydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1G308V/G308V mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1G308V/G308V mice, increased hepatic expression of αSMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling.en
dc.identifier.citationCells 9.2 (2020): 281. <https://www.mdpi.com/2073-4409/9/2/281>
dc.identifier.doihttps://doi.org/10.3390/cells9020281
dc.identifier.issn2073-4409
dc.identifier.opus-id13329
dc.identifier.urihttps://open.fau.de/handle/openfau/13329
dc.identifier.urnurn:nbn:de:bvb:29-opus4-133293
dc.language.isoen
dc.publisherMDPI
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.de
dc.subjectcholestasis
dc.subjectliver fibrosis
dc.subjectbile salts
dc.subjecthepatic stellate cell
dc.subjectEGFR
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleGlycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasisen
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.date.prevpublished2020-01-23
local.journal.issue2
local.journal.titleCells
local.journal.volume9
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.importimport
local.subject.sammlungUniversität Erlangen-Nürnberg / Eingespielte Open Access Artikel / Eingespielte Open Access Artikel 2020
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