| First Author | Briansó-Llort L | Year | 2022 |
| Journal | J Cell Physiol | Volume | 237 |
| Issue | 9 | Pages | 3598-3613 |
| PubMed ID | 35762039 | Mgi Jnum | J:345516 |
| Mgi Id | MGI:7579564 | Doi | 10.1002/jcp.30818 |
| Citation | Brianso-Llort L, et al. (2022) Transforming growth factor-beta 1: A new factor reducing hepatic SHBG production in liver fibrosis. J Cell Physiol 237(9):3598-3613 |
| abstractText | 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 (CCl(4) ). Our results clearly showed that CCl(4) induced liver fibrosis and reduced SHBG production by reducing hepatocyte nuclear factor 4 alpha (HNF-4alpha). The SHBG reduction could be influenced by the increase in transforming growth factor-beta 1 (TGF-beta1), which was increased in mice developing liver fibrosis. Therefore, we decided to evaluate the role of TGF-beta1 in regulating hepatic SHBG production. Results obtained in both HepG2 cells and human SHBG transgenic mice showed that TGF-beta1 reduced significantly SHBG messenger RNA and protein levels. Mechanistically TGF-beta1 downregulated P1-HNF-4alpha isoforms and increased P2-HNF-4alpha isoforms via Smad3 and Stat3 pathways through TGF-beta1 receptor I, resulting in transcriptional repression of the SHBG gene. Taken together, we found for the first time that TGF-beta1 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. |
