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Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-02-20 , DOI: 10.1016/j.jhep.2020.02.005 Juan P Arab 1 , Daniel Cabrera 2 , Tejasav S Sehrawat 3 , Nidhi Jalan-Sakrikar 3 , Vikas K Verma 3 , Douglas Simonetto 3 , Sheng Cao 3 , Usman Yaqoob 3 , Jonathan Leon 4 , Mariela Freire 4 , Jose I Vargas 4 , Thiago M De Assuncao 3 , Jung H Kwon 3 , Yi Guo 3 , Enis Kostallari 3 , Qing Cai 5 , Tatiana Kisseleva 6 , Youngman Oh 5 , Marco Arrese 4 , Robert C Huebert 3 , Vijay H Shah 3
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-02-20 , DOI: 10.1016/j.jhep.2020.02.005 Juan P Arab 1 , Daniel Cabrera 2 , Tejasav S Sehrawat 3 , Nidhi Jalan-Sakrikar 3 , Vikas K Verma 3 , Douglas Simonetto 3 , Sheng Cao 3 , Usman Yaqoob 3 , Jonathan Leon 4 , Mariela Freire 4 , Jose I Vargas 4 , Thiago M De Assuncao 3 , Jung H Kwon 3 , Yi Guo 3 , Enis Kostallari 3 , Qing Cai 5 , Tatiana Kisseleva 6 , Youngman Oh 5 , Marco Arrese 4 , Robert C Huebert 3 , Vijay H Shah 3
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Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice. Mice with HSC-selective deletion of NRP (Col/) or synectin (Col/synectin) paired or synectin mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated. Col/ mice showed less fibrosis, as expected, but also less inflammation and steatosis, with lower hepatic triglyceride content. Similar results were observed in the synectin model. Hepatocytes treated with supernatant of HSCs from Col/ mice compared to supernatant from mice were protected against ethanol-induced lipid droplet formation. An adipokine and inflammatory protein array from the supernatant of HSCs with NRP-1 knockdown showed a significant reduction in Igfbp3 (a major insulin-like growth factor-binding protein with multiple metabolic functions) and an increase in SerpinA12 (a serine-protease inhibitor) secretion compared to wild-type HSCs. Recombinant Igfbp3 induced lipid droplets, triglyceride accumulation, and lipogenic genes in hepatocytes while SerpinA12 was protective against ethanol-induced steatosis. Finally, Igfbp3 was increased, and SerpinA12 was decreased in serum and liver tissue from patients with alcoholic hepatitis. Selective deletion of NRP-1 from HSCs attenuates alcohol-induced steatohepatitis through regulation of Igfbp3 and SerpinA12 signaling. Hepatic stellate cells are known for their role in fibrosis (scarring of the liver). In this study, we describe their role in the modulation of fat deposition and inflammation in the liver, which occurs secondary to alcohol damage.
中文翻译：
肝星状细胞活化通过 Igfbp3 和 SerpinA12 促进酒精诱导的脂肪性肝炎
脂肪性肝炎会导致酒精相关肝病的纤维化。最近的研究表明，肝星状细胞（HSC）可能调节肝纤维化之前的实质细胞损伤和炎症，但其机制尚未完全明确。 Neuropilin-1 (NRP-1) 和 Synectin 是参与 HSC 激活的膜蛋白。在这项研究中，我们以破坏 NRP-1 和 Synectin 作为模型来评估 HSC 激活对小鼠酒精喂养引起的脂肪性肝炎发展的作用。 HSC 选择性删除 NRP (Col/) 或 Synectin (Col/synectin) 配对的小鼠或 Synectin 小鼠被喂食对照饮食或慢性/酗酒喂养模型。评估了脂肪变性和炎症的几种标志物。正如预期的那样，Col/ 小鼠表现出较少的纤维化，但炎症和脂肪变性也较少，肝甘油三酯含量较低。在联连蛋白模型中观察到类似的结果。与来自小鼠的上清液相比，用来自Col/小鼠的HSC上清液处理的肝细胞可以免受乙醇诱导的脂滴形成。来自 NRP-1 敲低的 HSC 上清液的脂肪因子和炎症蛋白阵列显示 Igfbp3（一种具有多种代谢功能的主要胰岛素样生长因子结合蛋白）显着减少，而 SerpinA12（一种丝氨酸蛋白酶抑制剂）增加与野生型 HSC 相比的分泌情况。重组 Igfbp3 诱导肝细胞中的脂滴、甘油三酯积累和脂肪生成基因，而 SerpinA12 可以防止乙醇诱导的脂肪变性。最后，酒精性肝炎患者血清和肝组织中 Igfbp3 升高，SerpinA12 降低。 从 HSC 中选择性删除 NRP-1 可通过调节 Igfbp3 和 SerpinA12 信号传导来减轻酒精诱导的脂肪性肝炎。肝星状细胞因其在纤维化（肝脏疤痕）中的作用而闻名。在这项研究中，我们描述了它们在调节肝脏脂肪沉积和炎症（继发于酒精损伤）中的作用。
更新日期：2020-02-20
中文翻译：
肝星状细胞活化通过 Igfbp3 和 SerpinA12 促进酒精诱导的脂肪性肝炎
脂肪性肝炎会导致酒精相关肝病的纤维化。最近的研究表明，肝星状细胞（HSC）可能调节肝纤维化之前的实质细胞损伤和炎症，但其机制尚未完全明确。 Neuropilin-1 (NRP-1) 和 Synectin 是参与 HSC 激活的膜蛋白。在这项研究中，我们以破坏 NRP-1 和 Synectin 作为模型来评估 HSC 激活对小鼠酒精喂养引起的脂肪性肝炎发展的作用。 HSC 选择性删除 NRP (Col/) 或 Synectin (Col/synectin) 配对的小鼠或 Synectin 小鼠被喂食对照饮食或慢性/酗酒喂养模型。评估了脂肪变性和炎症的几种标志物。正如预期的那样，Col/ 小鼠表现出较少的纤维化，但炎症和脂肪变性也较少，肝甘油三酯含量较低。在联连蛋白模型中观察到类似的结果。与来自小鼠的上清液相比，用来自Col/小鼠的HSC上清液处理的肝细胞可以免受乙醇诱导的脂滴形成。来自 NRP-1 敲低的 HSC 上清液的脂肪因子和炎症蛋白阵列显示 Igfbp3（一种具有多种代谢功能的主要胰岛素样生长因子结合蛋白）显着减少，而 SerpinA12（一种丝氨酸蛋白酶抑制剂）增加与野生型 HSC 相比的分泌情况。重组 Igfbp3 诱导肝细胞中的脂滴、甘油三酯积累和脂肪生成基因，而 SerpinA12 可以防止乙醇诱导的脂肪变性。最后，酒精性肝炎患者血清和肝组织中 Igfbp3 升高，SerpinA12 降低。 从 HSC 中选择性删除 NRP-1 可通过调节 Igfbp3 和 SerpinA12 信号传导来减轻酒精诱导的脂肪性肝炎。肝星状细胞因其在纤维化（肝脏疤痕）中的作用而闻名。在这项研究中，我们描述了它们在调节肝脏脂肪沉积和炎症（继发于酒精损伤）中的作用。
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