Mice with HSC-selective deletion of NRP (ColCre/Nrp1loxP) or synectin (ColCre/synectinloxP) vs. paired Nrp1loxP or synectinloxP mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated.
ColCre/Nrp1loxP 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 ColCre/Nrp1loxP mice compared to supernatant from Nrp1loxP 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 in vitro, 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.
HSC选择性缺失NRP(ColCre/Nrp1loxP)或synectin(ColCre/synectinloxP)的小鼠与给配对的Nrp1loxP或synectinloxP小鼠喂食对照饮食或慢性/暴饮暴食酒精喂养模型。评估了脂肪变性和炎症的几种标志物。
ColCre/Nrp1loxP小鼠显示较少的纤维化,正如预期的那样,但也减少了炎症和脂肪变性,肝脏甘油三酯含量较低。在synectin模型中观察到类似的结果。与来自Nrp1loxP小鼠的上清液相比,用来自ColCre/Nrp1loxP小鼠的HSC的上清液处理的肝细胞被保护免受乙醇诱导的脂滴形成。来自具有NRP-1敲低的HSC的上清液的脂肪因子和炎性蛋白阵列显示,与野生型HSC相比,Igfbp3(具有多种代谢功能的主要胰岛素样生长因子结合蛋白)的显著减少和SerpinA12(丝氨酸蛋白酶抑制剂)分泌的增加。重组Igfbp3诱导的脂滴,甘油三酯积累,和体外肝细胞中的脂肪生成基因,而SerpinA12对乙醇诱导的脂肪变性具有保护作用。最后,Igfbp3增加,酒精性肝炎患者的血清和肝组织中SerpinA12降低。
从HSC选择性缺失NRP-1通过调节Igfbp3和SerpinA12信号传导减弱酒精诱导的脂肪性肝炎。
肝星状细胞在纤维化(肝瘢痕形成)中的作用是众所周知的。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中的作用,这是继发于酒精损伤的。