a Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou , China.
Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):1984-1994. doi: 10.1080/21691401.2019.1615931.
Recently, we showed that parathyroid hormone-like hormone (PTHLH), a cytokine-like polyprotein, is critical for extracellular matrix (ECM) deposition through the activation of hepatic stellate cells (HSCs). Here, we show that N-terminal PTHLH is secreted into the supernatant of injured hepatocytes, its expression is positively correlated with liver fibrosis severity based on mice liver biopsies, and it is primarily expressed in the cytoplasm of hepatocytes along the fibrous septa of fibrotic livers. PTHLH overexpression in mice was achieved through adeno-associated virus-mediated gene delivery (AAV9-PTHLH), and liver fibrosis was induced with carbon tetrachloride (CCl). We observed that AAV9-PTHLH induced spontaneous development of liver fibrosis and increased sensitivity to CCl. PTHLH increased Hedgehog (Hh) pathway activation in a PTH1R-dependent manner, and the effect of PTHLH was primarily mediated by protein kinase C (PKC) . PTHLH-mediated PTH1R-PKC pathway activation is a key event in the profibrotic Hh-dependent activation of HSCs.
最近，我们发现甲状旁腺激素样激素（PTHLH）是一种细胞因子样多蛋白，通过激活肝星状细胞（HSCs）对细胞外基质（ECM）的沉积起关键作用。在这里，我们发现 N 端 PTHLH 分泌到受损肝细胞的上清液中，其表达与基于小鼠肝活检的肝纤维化严重程度呈正相关，并且主要表达在纤维化肝脏纤维间隔处的肝细胞细胞质中。通过腺相关病毒介导的基因传递（AAV9-PTHLH）在小鼠中过表达 PTHLH，并使用四氯化碳（CCl）诱导肝纤维化。我们观察到 AAV9-PTHLH 诱导肝纤维化的自发发展，并增加对 CCl 的敏感性。PTHLH 以 PTH1R 依赖的方式增加 Hedgehog（Hh）通路的激活，而 PTHLH 的作用主要是通过蛋白激酶 C（PKC）介导的。PTHLH 介导的 PTH1R-PKC 通路激活是 Hh 依赖性激活 HSCs 致纤维化的关键事件。
