Transforming growth factor-beta 1: A new factor reducing hepatic SHBG production in liver fibrosis

Low plasma sex hormone-binding globulin (SHBG) levels are present in fatty liver disease, which represents a spectrum of diseases ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. 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 SHBG transgenic mice developing liver fibrosis induced by carbon tetrachloride (CCI4). Our results clearly showed that CCI4 induced liver fibrosis and reduced SHBG production by reducing hepatocyte nuclear factor 4 alpha (HNF-4 alpha). The SHBG reduction could be influenced by the increase in transforming growth factor-beta 1 (TGF-beta 1), which was increased in mice developing liver fibrosis. Therefore, we decided to evaluate the role of TGF-beta 1 in regulating hepatic SHBG production. Results obtained in both HepG2 cells and human SHBG transgenic mice showed that TGF-beta 1 reduced significantly SHBG messenger RNA and protein levels. Mechanistically TGF-beta 1 downregulated P1-HNF-4 alpha isoforms and increased P2-HNF-4 alpha isoforms via Smad3 and Stat3 pathways through TGF-beta 1 receptor I, resulting in transcriptional repression of the SHBG gene. Taken together, we found for the first time that TGF-beta 1 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.