Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2
Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2
复制标题
DOI：
10.1097/hep.0000000000000333
复制
发表时间：
2023-03
期刊：
影响因子：
13.5
通讯作者：
Ting Hong;X. Xiong;Yaqiong Chen;Qiuyu Wang;Xiao Fu;Qingnan Meng;Yan Lu;Xiaoying Li
中科院分区：
文献类型：
--
作者：
Ting Hong;X. Xiong;Yaqiong Chen;Qiuyu Wang;Xiao Fu;Qingnan Meng;Yan Lu;Xiaoying Li
背景和目标：甲状旁腺激素受体-1（PTH 1 R）是一种B G类蛋白偶联受体，对骨骼发育、骨转换和钙稳态起重要作用。然而，PTH 1 R信号在肝纤维化中的作用在很大程度上是未知的。在这里，PTH 1 R信号传导在HSC活化和肝纤维化中的作用被检查。方法和结果：使用人肝标本或四氯化碳（CCl 4）处理或蛋氨酸和胆碱缺乏饮食（MCD）喂养的C57/BL 6小鼠，PTH 1 R在活化的HSC和纤维化肝脏中高度表达。肝硬化患者肝组织中PTH 1 R mRNA水平与α-平滑肌肌动蛋白（α-smooth muscle actin）表达呈正相关。HSC特异性PTH 1 R缺失的小鼠免受CCl 4、MCD或西方饮食以及低剂量CCl 4诱导的肝纤维化的影响。相反，甲状旁腺激素（PTH）加重肝纤维化的四氯化碳治疗的小鼠。小鼠原代HSC和LX 2细胞系用于体外实验。通过荧光素酶报告基因分析和染色质免疫沉淀分析结合mRNA测序在HSC中进行的分子分析显示，cAMP反应元件结合蛋白样2（Crebl 2），一种在PTH处理的HSC中的新型调节剂，与母亲针对十肢瘫痪同源物3（SMAD 3）相互作用，并在活化HSC和胶原沉积中增加TGFβ的转录。与此一致，HSC特异性Crebl 2缺失改善了CCl 4处理小鼠中PTH诱导的肝纤维化。结论：在小鼠和人类模型中，我们发现PTH 1 R在活化的HSC和纤维化肝脏中高度表达。PTH 1 R信号通过Creb 12/SMAD 3/TGFβ调节通路调节HSC中胶原的产生。阻断HSC中PTH 1 R信号可能有助于减轻肝纤维化的发展。
Background and Aims: 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. Approach and Results: PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl4)-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 CCl4, MCD, or western diet, plus low-dose CCl4-induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl4-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 CCl4-treated mice. Conclusions: 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.