Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.
Hepatology. 2013 May;57(5):1793-805. doi: 10.1002/hep.26219. Epub 2013 Mar 14.
The pathophysiology of nonalcoholic steatohepatitis (NASH) should be approached as a multifactorial process. In several stages of NASH, a link between disease progression and hepatic microvasculature changes can be made. In this study we investigated the role of angiogenesis in two mouse models for NASH, and the effect of a preventive and therapeutic antiangiogenic treatment in a diet-induced mouse model for NASH. Protein and RNA levels of angiogenic and inflammatory factors were significantly up-regulated in the liver of C56BL/6 and db/db mice with NASH at different timepoints. To examine the effect of angiogenic factors on the disease progression of NASH, a prevention and treatment study was set up, blocking the placental growth factor (PlGF) or vascular endothelial growth factor receptor 2 (VEGFR2). Our study showed that treatment prevents the progression of NASH by attenuating steatosis and inflammation, both in a preventive and therapeutic setting, thereby confirming the hypothesis that angiogenic factors play an early role in the disease progression from steatosis to NASH. Anti-PlGF (αPlGF) did not significantly improve liver histology. Vascular corrosion casting showed a more disrupted liver vasculature in mice with NASH compared to controls. Treatment with αVEGFR2 showed an improvement of the liver vasculature. Moreover, fat-laden primary hepatocytes treated with αVEGFR2 stored significantly less lipids.
Our results demonstrate that there is an increased expression of angiogenic factors in the liver in different mouse models for NASH. We found that VEGFR2 blockage attenuates steatosis and inflammation in a diet-induced mouse model for NASH in a preventive and therapeutic setting. Our findings warrant further investigation of the role of angiogenesis in the pathophysiology in NASH.
非酒精性脂肪性肝炎 (NASH) 的病理生理学应被视为一个多因素的过程。在 NASH 的几个阶段，可以在疾病进展和肝微血管变化之间建立联系。在这项研究中，我们研究了血管生成在两种 NASH 小鼠模型中的作用，以及在饮食诱导的 NASH 小鼠模型中预防和治疗性抗血管生成治疗的效果。在不同时间点，NASH 的 C56BL/6 和 db/db 小鼠肝脏中的血管生成和炎症因子的蛋白和 RNA 水平显著上调。为了研究血管生成因子对 NASH 疾病进展的影响，我们进行了一项预防和治疗研究，阻断胎盘生长因子 (PlGF) 或血管内皮生长因子受体 2 (VEGFR2)。我们的研究表明，该治疗通过减轻脂肪变性和炎症来预防 NASH 的进展，无论是在预防还是治疗环境中，从而证实了血管生成因子在从脂肪变性到 NASH 的疾病进展中早期发挥作用的假说。抗-PlGF (αPlGF) 并未显著改善肝组织学。血管腐蚀铸造显示，与对照组相比，NASH 小鼠的肝脏血管更紊乱。αVEGFR2 的治疗改善了肝脏血管。此外，用αVEGFR2 处理富含脂肪的原代肝细胞可显著减少脂肪储存。
我们的结果表明，在不同的 NASH 小鼠模型中，肝脏中血管生成因子的表达增加。我们发现，VEGFR2 阻断在饮食诱导的 NASH 小鼠模型中以预防和治疗的方式减轻脂肪变性和炎症。我们的研究结果证明，血管生成在 NASH 的病理生理学中发挥着重要作用，值得进一步研究。
