Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.
Human Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
J Cell Physiol. 2022 Sep;237(9):3598-3613. doi: 10.1002/jcp.30818. Epub 2022 Jun 27.
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 ). Our results clearly showed that CCl 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.
低血浆性激素结合球蛋白 (SHBG) 水平存在于脂肪性肝病中，它代表了一系列疾病，从肝细胞脂肪变性到脂肪性肝炎、纤维化和不可逆转的肝硬化。我们之前已经确定，脂肪堆积会减少不同非酒精性脂肪性肝病小鼠模型中的 SHBG 产生。在目前的工作中，我们有兴趣阐明导致肝纤维化时降低 SHBG 血浆水平的分子机制。为此，使用人 SHBG 转基因小鼠进行了体内研究，这些小鼠发展为四氯化碳 (CCl ) 诱导的肝纤维化。我们的结果清楚地表明，CCl 诱导的肝纤维化通过减少肝细胞核因子 4 阿尔法 (HNF-4α) 降低了 SHBG 的产生。SHBG 的减少可能受到转化生长因子-β1 (TGF-β1) 的增加的影响，TGF-β1 在发生肝纤维化的小鼠中增加。因此，我们决定评估 TGF-β1 在调节肝 SHBG 产生中的作用。在 HepG2 细胞和人 SHBG 转基因小鼠中获得的结果表明，TGF-β1 显著降低了 SHBG 信使 RNA 和蛋白水平。从机制上讲，TGF-β1 通过 TGF-β1 受体 I 下调 P1-HNF-4α 异构体并增加 P2-HNF-4α 异构体，通过 Smad3 和 Stat3 途径，导致 SHBG 基因的转录抑制。综上所述，我们首次发现 TGF-β1 是调节肝纤维化中肝 SHBG 产生的新因子。需要进一步研究以确定这种肝 SHBG 产生减少在非酒精性脂肪性肝炎进展中的作用。
