The deficient sinusoidal drainage is strongly associated with adherence of leukocytes to sinusoidal endothelial cells and can result inexpression of increased hepatic ICAM-1,VEGFR-2,Cdh5, CD34, CD31, E-selectin and other molecular mediators for leukocyte extravasation and transendothelial migration. Hepatic ICAM-1 and E-selectin are expressed on the endothelial cells and are included in the category of cell adhesion molecules induced by VEGF, thus helping intransendothelial migration and leukocyte infiltration. The events that follow might form secondary inflammatory foci in the hepatic sinusoidal areas, thus increasing the risk of collagen deposition. Leptin, an adipokine produced in the liver and the adipose tissue, is Perindopril Erbumine thought to contribute, in part, to NASH development in obesity Amifostine through its proinflammatory actions on sinusoidal epithelial cells and Kupffer cells. Recent lines of evidence support the role of elevated levels of leptin found in obesity in generating reactive oxygen and reactive nitrogen species and subsequent free radical formation. The presence of high levels of leptin in obesity certainly makes it a prime candidate for amplifying the risk of NASH progression as both a first and second hit, which not only satisfies the two-hit hypothesis, but also is in line with the multi-hit paradigm. Our own studies have demonstrated that leptin mediates the effect on NASH progression through peroxynitrite formation and Kupffer cell activation in a toxin model of NASH. Leptin has been found to promote fibrosis by its effect on stellate cell proliferation. Further leptin has been implicated in endothelial dysfunction of obesity and neovascularization in NASH. Hepatic neovascularization and expression of vascular endothelial growth factor, a potent angiogenic factor were increased in NASH models but absent in rats that did not have leptin. Endothelial dysfunction has been recently shown to bean early incidence in NASH progression. Since elevated leptin has a role in endothelial dysfunction, proinflammatory and profibrotic action in mediating NASH progression, it will be important to see whether it can regulate these pathways through epigenetic modulation, especially by up regulating microRNAs.