First, selleck chemicals we will discuss the physiological part in the development of NASH. Lipotoxicity

activates cytokines, which will subsequently induce recruitment of inflammatory cells and platelets. Inflammation triggers vascular permeability by recruiting monocytes, macrophages, platelets, mast cells, and other leukocytes. These cells can initiate angiogenesis through different pathways. In this manner, inflammation can contribute to the formation of new vascular structures in the liver.26 Second, angiogenesis could also be triggered mechanically as fat accumulation damages the hepatocytes leading to deregulation of the microvascular blood flow. Reduction in sinusoidal perfusion initially arises from the effects of hepatocytes loaded with accumulated lipids. This results in reduction of the intrasinusoidal volume, selleck chemical as well as altering the sinusoidal architecture.27 Vascular corrosion casting has recently been revived and has proven to be an excellent tool for detailed 3D morphological examination of normal and pathological microcirculation.28 Another factor that should be taken into account is the activation of HSC, as it has been associated with fibrosis and angiogenesis.29 It has been

shown that angiogenic factors are up-regulated in various chronic liver diseases with endstage liver fibrosis.10 However, in our study HSC activation is probably not the main trigger for angiogenesis as immunohistochemical staining for aSMA only showed mild activation of HSC. This can be explained due to the fact that our mice only developed a stage 1 fibrosis after 8 weeks of the MCD diet. Furthermore, we found that levels of VEGF and CD105 are already significantly increased after 3 days and 1 week of MCD diet in db/db and C57BL6/J mice, respectively.24 At that time liver histology showed increased steatosis, ballooning, and inflammation. However, mice could not yet be classified as NASH. These results suggest that the molecular events associated with an up-regulation

of angiogenic factors start very early in the pathophysiology Idelalisib in vivo of NASH. Our study confirmed that during the pathophysiology of NASH there is both a physiological and a mechanical trigger that induces angiogenesis. As such, we found a significant increase of inflammatory and angiogenic factors in two mouse models early in the development of NASH. Electron microscopic images of the vascular corrosion casts of the liver of mice with NASH clearly show that the morphology of the vasculature is disrupted compared to controls. However, it is not clear what the primary trigger for angiogenesis in the pathophysiology of NASH is. Probably this phenomenon should be addressed as a multifactorial process in which the combination of forces affecting the mechanotransduction in the endothelium and physiological changes in the lipogenic and inflammatory metabolism causes the initiation of angiogenesis.