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dc.contributor.authorChen, Jennifer Y.en_US
dc.contributor.authorNewcomb, Benjaminen_US
dc.contributor.authorZhou, Chanen_US
dc.contributor.authorPondick, Joshua V.en_US
dc.contributor.authorGhoshal, Saranien_US
dc.contributor.authorYork, Samuel R.en_US
dc.contributor.authorMotola, Daniel L.en_US
dc.contributor.authorCoant, Nicolasen_US
dc.contributor.authorYi, Jae Kyoen_US
dc.contributor.authorMao, Cunguien_US
dc.contributor.authorTanabe, Kenneth K.en_US
dc.contributor.authorBronova, Irinaen_US
dc.contributor.authorBerdyshev, Evgeny V.en_US
dc.contributor.authorFuchs, Bryan C.en_US
dc.contributor.authorHannun, Yusufen_US
dc.contributor.authorChung, Raymond T.en_US
dc.contributor.authorMullen, Alan C.en_US
dc.date.accessioned2017-04-06T03:19:23Z
dc.date.issued2017en_US
dc.identifier.citationChen, J. Y., B. Newcomb, C. Zhou, J. V. Pondick, S. Ghoshal, S. R. York, D. L. Motola, et al. 2017. “Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.” Scientific Reports 7 (1): 44867. doi:10.1038/srep44867. http://dx.doi.org/10.1038/srep44867.en
dc.identifier.issnen
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:32072075
dc.description.abstractActivation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.en
dc.language.isoen_USen
dc.publisherNature Publishing Groupen
dc.relation.isversionofdoi:10.1038/srep44867en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359599/pdf/en
dash.licenseLAAen_US
dc.titleTricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cellsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalScientific Reportsen
dash.depositing.authorChen, Jennifer Y.en_US
dc.date.available2017-04-06T03:19:23Z
dc.identifier.doi10.1038/srep44867*
dash.authorsorderedfalse
dash.contributor.affiliatedGhoshal, Sarani
dash.contributor.affiliatedZhou, Chan
dash.contributor.affiliatedMullen, Alan
dash.contributor.affiliatedChen, Jennifer Yin-zu
dash.contributor.affiliatedTanabe, Kenneth
dash.contributor.affiliatedFuchs, Bryan
dash.contributor.affiliatedChung, Raymond


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