当前位置: X-MOL 学术Hepatology › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
PGD2/DP1 axis promotes liver regeneration by secreting Wnt2 in Kupffer cells in mice
Hepatology ( IF 12.9 ) Pub Date : 2024-07-19 , DOI: 10.1097/hep.0000000000001020
Juanjuan Li 1, 2, 3, 4 , Yinghong Zheng 1 , Zhenzhen Duan 2 , Qingye Zeng 5 , Jin Qu 6 , Jincheng Zhang 2 , Jiao Liu 1 , Wenlong Shang 1 , Xixi Tao 1 , Tingting Yu 1 , Xinzhi Li 7 , Lifu Wang 4 , Liming Yang 8 , Deping Kong 2 , Ying Yu 1
Affiliation  

Background and aims: The liver possesses a remarkable regenerative capacity in response to injuries or viral infections. Various growth factors and cytokines are involved in regulating liver regeneration. Prostaglandin (PG) D2, a pro-resolution lipid mediator, is the most abundant hepatic prostanoid. However, the role of PGD2 in the injury-induced liver regeneration remains unclear. Approach and results: Two-thirds partial hepatectomy (70% PH), massive hepatectomy (85% resection), and carbon tetrachloride-induced chronic injury were performed in mice to study the mechanisms of live regeneration. Hepatic PGD2 production was elevated in mice after PH. Global deletion of D prostanoid receptor (DP) 1, but not DP2, slowed PH-induced liver regeneration in mice, as evidenced by lower liver weight to body weight ratio, less Ki67+ hepatocyte proliferation, and G2/M phase hepatocytes. Additionally, DP1 deficiency specifically in resident Kupffer cells (KCs), and not in endothelial cells or hepatic stellate cells, retarded liver regeneration in mice post-PH. Conversely, the overexpression of exogenous DP1 in KCs accelerated liver regeneration in mice. Mechanistically, DP1 activation promoted Wnt2 transcription in a PKA/CREB-dependent manner in resident KCs and mediated hepatocyte proliferation through Frizzled8/β-catenin signaling. Adeno-associated virus vector serotype 8 (AAV8)-mediated Frizzled8 knockdown in hepatocytes attenuated accelerated liver regeneration in KC-DP1 transgenic mice post-PH. Treatment with the DP1 receptor agonist BW245C promotes PH-induced liver regeneration in mice. Conclusions: DP1 activation mediates crosstalk between KCs and hepatocytes through Wnt2, and facilitates liver regeneration. Hence, DP1 may serve as a novel therapeutic target in acute and chronic liver diseases.

中文翻译:


PGD​​2/DP1轴通过分泌Wnt2促进小鼠库普弗细胞肝再生



背景和目的:肝脏对损伤或病毒感染具有显着的再生能力。多种生长因子和细胞因子参与调节肝再生。前列腺素 (PG) D 2是一种促分解脂质介质,是最丰富的肝脏前列腺素。然而,PGD 的作用2在损伤诱导的肝再生中的作用仍不清楚。方法和结果:对小鼠进行三分之二部分肝切除术(70% PH)、大量肝切除术(85% 切除)和四氯化碳诱导的慢性损伤,以研究活体再生机制。肝脏胚胎植入前诊断2 PH后小鼠的产量升高。整体删除 D 类前列腺素受体 (DP) 1(而非 DP2)会减慢 PH 诱导的小鼠肝再生,肝重与体重比降低、Ki67 减少就证明了这一点+肝细胞增殖和G2/M期肝细胞。此外,DP1 缺乏(特别是常驻库普弗细胞 (KC))而非内皮细胞或肝星状细胞中的缺乏,会延迟 PH 后小鼠的肝脏再生。相反,KC 中外源 DP1 的过度表达加速了小鼠的肝脏再生。从机制上讲,促进 DP1 激活Wnt2在常驻 KC 中以 PKA/CREB ​​依赖性方式转录,并通过 Frizzled8/β-连环蛋白信号传导介导肝细胞增殖。腺相关病毒载体血清型 8 (AAV8) 介导的肝细胞中的 Frizzled8 敲低可减弱 KC-DP1 转基因小鼠 PH 后的加速肝再生。 DP1 受体激动剂 BW245C 治疗可促进 PH 诱导的小鼠肝脏再生。 结论:DP1激活通过Wnt2介导KCs和肝细胞之间的串扰,促进肝再生。因此,DP1可能作为急慢性肝病的新治疗靶点。
更新日期:2024-07-19
down
wechat
bug