{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T14:01:49Z","timestamp":1770040909416,"version":"3.49.0"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["1K08HL077533"],"award-info":[{"award-number":["1K08HL077533"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["PPAR Research"],"published-print":{"date-parts":[[2012]]},"abstract":"<jats:p>Transforming growth factor<jats:italic>\u03b2<\/jats:italic>1 (TGF<jats:italic>\u03b2<\/jats:italic>1) promotes fibrosis by, among other mechanisms, activating quiescent fibroblasts into myofibroblasts and increasing the expression of extracellular matrices. Recent work suggests that peroxisome proliferator-activated receptor<jats:italic>\u03b3<\/jats:italic>(PPAR<jats:italic>\u03b3<\/jats:italic>) is a negative regulator of TGF<jats:italic>\u03b2<\/jats:italic>1-induced fibrotic events. We, however, hypothesized that antifibrotic pathways mediated by PPAR<jats:italic>\u03b3<\/jats:italic>are influenced by TGF<jats:italic>\u03b2<\/jats:italic>1, causing an imbalance towards fibrogenesis. Consistent with this, primary murine primary lung fibroblasts responded to TGF<jats:italic>\u03b2<\/jats:italic>1 with a sustained downregulation of PPAR<jats:italic>\u03b3<\/jats:italic>transcripts. This effect was dampened in lung fibroblasts deficient in Smad3, a transcription factor that mediates many of the effects of TGF<jats:italic>\u03b2<\/jats:italic>1. Paradoxically, TGF<jats:italic>\u03b2<\/jats:italic>1 stimulated the activation of the PPAR<jats:italic>\u03b3<\/jats:italic>gene promoter and induced the phosphorylation of PPAR<jats:italic>\u03b3<\/jats:italic>in primary lung fibroblasts. The ability of TGF<jats:italic>\u03b2<\/jats:italic>1 to modulate the transcriptional activity of PPAR<jats:italic>\u03b3<\/jats:italic>was then tested in NIH\/3T3 fibroblasts containing a PPAR<jats:italic>\u03b3<\/jats:italic>-responsive luciferase reporter. In these cells, stimulation of TGF<jats:italic>\u03b2<\/jats:italic>1 signals with a constitutively active TGF<jats:italic>\u03b2<\/jats:italic>1 receptor transgene blunted PPAR<jats:italic>\u03b3<\/jats:italic>-dependent reporter expression induced by troglitazone, a PPAR<jats:italic>\u03b3<\/jats:italic>activator. Overexpression of PPAR<jats:italic>\u03b3<\/jats:italic>prevented TGF<jats:italic>\u03b2<\/jats:italic>1 repression of troglitazone-induced PPAR<jats:italic>\u03b3<\/jats:italic>-dependent gene transcription, whereas coexpression of PPAR<jats:italic>\u03b3<\/jats:italic>and Smad3 transgenes recapitulated the TGF<jats:italic>\u03b2<\/jats:italic>1 effects. We conclude that modulation of PPAR<jats:italic>\u03b3<\/jats:italic>is controlled by TGF<jats:italic>\u03b2<\/jats:italic>1, in part through Smad3 signals, involving regulation of PPAR<jats:italic>\u03b3<\/jats:italic>expression and transcriptional potential.<\/jats:p>","DOI":"10.1155\/2012\/375876","type":"journal-article","created":{"date-parts":[[2012,9,10]],"date-time":"2012-09-10T21:01:31Z","timestamp":1347310891000},"page":"1-7","source":"Crossref","is-referenced-by-count":19,"title":["TGF<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\"><mml:mrow><mml:mi mathvariant=\"bold-italic\">\u03b2<\/mml:mi><\/mml:mrow><\/mml:math>1 Controls PPAR<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\"><mml:mrow><mml:mi mathvariant=\"bold\">\u03b3<\/mml:mi><\/mml:mrow><\/mml:math>Expression, Transcriptional Potential, and Activity, in Part, through Smad3 Signaling in Murine Lung Fibroblasts"],"prefix":"10.1155","volume":"2012","author":[{"given":"Allan","family":"Ramirez","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Disorders, Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin N.","family":"Ballard","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Disorders, Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse","family":"Roman","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Disorders, Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40202, USA"},{"name":"Pulmonary Section, Medicine Service, Robley Rex Veterans Affairs Medical Center, Louisville, KY 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","reference":[{"issue":"8","key":"1","doi-asserted-by":"crossref","first-page":"5390","DOI":"10.4049\/jimmunol.175.8.5390","volume":"175","year":"2005","journal-title":"Journal of Immunology"},{"key":"2","first-page":"365","volume-title":"Cytokine biology and the pathogenesis of interstitial lung disease","year":"2011"},{"issue":"4","key":"3","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1172\/JCI119590","volume":"100","year":"1997","journal-title":"Journal of Clinical Investigation"},{"issue":"10","key":"4","doi-asserted-by":"crossref","first-page":"5693","DOI":"10.4049\/jimmunol.163.10.5693","volume":"163","year":"1999","journal-title":"Journal of Immunology"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.3109\/08977194.2011.595714"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00163.2007"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2006.01430.x"},{"issue":"3","key":"8","doi-asserted-by":"crossref","first-page":"L585","DOI":"10.1152\/ajplung.00151.2001","volume":"282","year":"2002","journal-title":"American Journal of Physiology. 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