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We have previously determined that fat accumulation reduces SHBG production in different nonalcoholic fatty liver disease mouse models. In the present work, we are interested in elucidating the molecular mechanisms reducing SHBG plasma levels in liver fibrosis. For this purpose, in vivo studies were performed using the human <jats:italic>SHBG<\/jats:italic> transgenic mice developing liver fibrosis induced by carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>). Our results clearly showed that CCl<jats:sub>4<\/jats:sub> induced liver fibrosis and reduced SHBG production by reducing hepatocyte nuclear factor 4 alpha (HNF\u20104\u03b1). The SHBG reduction could be influenced by the increase in transforming growth factor\u2010beta 1 (TGF\u2010\u03b21), which was increased in mice developing liver fibrosis. Therefore, we decided to evaluate the role of TGF\u2010\u03b21 in regulating hepatic SHBG production. Results obtained in both HepG2 cells and human <jats:italic>SHBG<\/jats:italic> transgenic mice showed that TGF\u2010\u03b21 reduced significantly SHBG\u00a0messenger RNA and protein levels. Mechanistically TGF\u2010\u03b21 downregulated P1\u2010HNF\u20104\u03b1 isoforms and increased P2\u2010HNF\u20104\u03b1 isoforms via Smad3 and Stat3 pathways through TGF\u2010\u03b21 receptor I, resulting in transcriptional repression of the <jats:italic>SHBG<\/jats:italic> gene. Taken\u00a0together, we found for the first time that TGF\u2010\u03b21 is a new factor regulating hepatic SHBG production in liver fibrosis. Further research is needed to determine the role of this reduction in hepatic SHBG production in the progression of nonalcoholic steatohepatitis.<\/jats:p>","DOI":"10.1002\/jcp.30818","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T06:13:11Z","timestamp":1656396791000},"page":"3598-3613","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Transforming growth factor\u2010beta 1: A new factor reducing hepatic SHBG production in liver fibrosis"],"prefix":"10.1002","volume":"237","author":[{"given":"Laura","family":"Brians\u00f3\u2010Llort","sequence":"first","affiliation":[{"name":"Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital Autonomous University of Barcelona Barcelona 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