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

• Published in: Journal of cellular physiology Vol. 237; no. 9; pp. 3598 - 3613
• Main Authors: Briansó‐Llort, Laura, Fuertes‐Rioja, Lidia, Ramos‐Perez, Lorena, Salcedo‐Allende, Maria Teresa, Hernandez, Cristina, Simó, Rafael, Selva, David M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc 01.09.2022
• Subjects: Animal models; Carbon tetrachloride; Cirrhosis; Fatty liver; Fibrosis; Gene silencing; Globulins; Growth factors; hepatic fibrosis; Hepatocyte nuclear factor 4; HNF‐4α isoforms; Human performance; In vivo methods and tests; Isoforms; Liver; Liver cirrhosis; Liver diseases; Molecular modelling; mRNA; Plasma levels; Reduction; Sex hormones; Smad3 protein; Stat3 protein; Steatosis; TGF‐β1; Transforming growth factor-b1; Transgenic animals; Transgenic mice; transgenic mice and HepG2 cells
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30818

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 (CCl4). Our results clearly showed that CCl4 induced liver fibrosis and reduced SHBG production by reducing hepatocyte nuclear factor 4 alpha (HNF‐4α). The SHBG reduction could be influenced by the increase in transforming growth factor‐beta 1 (TGF‐β1), which was increased in mice developing liver fibrosis. Therefore, we decided to evaluate the role of TGF‐β1 in regulating hepatic SHBG production. Results obtained in both HepG2 cells and human SHBG transgenic mice showed that TGF‐β1 reduced significantly SHBG messenger RNA and protein levels. Mechanistically TGF‐β1 downregulated P1‐HNF‐4α isoforms and increased P2‐HNF‐4α isoforms via Smad3 and Stat3 pathways through TGF‐β1 receptor I, resulting in transcriptional repression of the SHBG gene. Taken together, we found for the first time that TGF‐β1 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. During CCl4‐induced acute liver injury in mice, there is an increase in TGF‐β1 production. TGF‐β1 activates hepatic stellate cells which are responsible for collagen production. In hepatocytes, TGF‐β1 reduces P1‐HNF‐4α isoforms and increases P2‐HNF‐4α isoforms via Smad and Stat signaling pathways through TGF‐β1 receptor I, which, in turn, reduces SHBG expression in hepatocytes. KC, Kupffer cells; HSC, hepatic stellate cells; ECM, extracellular matrix.