Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, Institute of Translational Medicine, Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Hepatology. 2023 Dec 1;78(6):1763-1776. doi: 10.1097/HEP.0000000000000333. Epub 2023 Mar 21.
Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of HSCs and hepatic fibrosis was examined.
PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl 4 )-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl 4 , MCD, or western diet, plus low-dose CCl 4 -induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl 4 -treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of TGFβ in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl 4 -treated mice.
In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs through Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.
甲状旁腺激素受体 1（PTH1R）是一种 B 类 G 蛋白偶联受体，在骨骼发育、骨转换和钙稳态中起核心作用。然而，PTH1R 信号在肝纤维化中的作用在很大程度上尚不清楚。本文旨在研究 PTH1R 信号在 HSCs 激活和肝纤维化中的作用。
采用人肝组织标本或四氯化碳（CCl 4 ）处理或蛋氨酸和胆碱缺乏饮食（MCD）喂养的 C57/BL6 小鼠，发现 PTH1R 在激活的 HSCs 和纤维化肝脏中高表达。肝硬化患者肝组织 PTH1R 的 mRNA 水平与α-平滑肌肌动蛋白呈正相关。HSCs 特异性 PTH1R 缺失的小鼠可免受 CCl 4 、MCD 或西方饮食加低剂量 CCl 4 诱导的肝纤维化的影响。相反，甲状旁腺激素（PTH）加重了 CCl 4 处理的小鼠的肝纤维化。用于体外实验的小鼠原代 HSCs 和 LX2 细胞系。通过荧光素酶报告基因检测和染色质免疫沉淀检测与 HSCs 中 mRNA 测序相结合的分子分析表明，cAMP 反应元件结合蛋白样 2（Crebl2）是 PTH 处理的 HSCs 中的一种新型调节因子，它与母系抗颅面发育不全同源物 3（SMAD3）相互作用，增加 TGFβ 在激活 HSCs 中的转录和胶原沉积。一致的是，HSCs 特异性 Crebl2 缺失可减轻 CCl 4 处理的小鼠中 PTH 诱导的肝纤维化。
在小鼠和人类模型中，我们发现 PTH1R 在激活的 HSCs 和纤维化肝脏中高表达。PTH1R 信号通过 Crebl2/SMAD3/TGFβ 调节环调节 HSCs 中的胶原产生。阻断 HSCs 中的 PTH1R 信号可能有助于减轻肝纤维化的发展。
