Abstract
Hedgehog signaling pathway activation has been implicated in the pathogenesis of NASH. Despite this concept, hedgehog pathway inhibitors have not been explored. Thus, we examined the effect of vismodegib, a hedgehog signaling pathway inhibitor, in a diet-induced model of NASH. C57BL/6 mice were placed on 3-month chow or FFC (high saturated fats, fructose, and cholesterol) diet. One week prior to sacrifice, mice were treated with vismodegib or vehicle. Mice fed the FFC diet developed significant steatosis, which was unchanged by vismodegib therapy. In contrast, vismodegib significantly attenuated FFC-induced liver injury as manifested by reduced serum ALT and hepatic TUNEL-positive cells. In line with the decreased apoptosis, vismodegib prevented FFC-induced strong upregulation of death receptor DR5 and its ligand TRAIL. In addition, FFC-fed mice, but not chow-fed animals, underwent significant liver injury and apoptosis following treatment with a DR5 agonist; however, this injury was prevented by pre-treatment with vismodegib. Consistent with a reduction in liver injury, vismodegib normalized FFC-induced markers of inflammation including mRNA for TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and a variety of macrophage markers. Furthermore, vismodegib in FFC-fed mice abrogated indices of hepatic fibrogenesis. In conclusion, inhibition of hedgehog signaling with vismodegib appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition may be salutary in human NASH.
Highlights
With the increasing prevalence of obesity, nonalcoholic fatty liver disease has become the most common form of chronic liver disease in Western countries [1]
A subset of patients with nonalcoholic fatty liver disease progress to nonalcoholic steatohepatitis (NASH), a more aggressive form of the disease characterized by hepatocyte apoptosis, hepatic infiltration by inflammatory cells and fibrosis, which may culminate in liver cirrhosis and the development of hepatocellular carcinoma
The principal findings of this study provide mechanistic insights regarding the efficacy of a clinically relevant, pharmacologic smoothened inhibitor vismodegib in a murine model of NASH
Summary
With the increasing prevalence of obesity, nonalcoholic fatty liver disease has become the most common form of chronic liver disease in Western countries [1]. A subset of patients with nonalcoholic fatty liver disease progress to nonalcoholic steatohepatitis (NASH), a more aggressive form of the disease characterized by hepatocyte apoptosis, hepatic infiltration by inflammatory cells and fibrosis, which may culminate in liver cirrhosis and the development of hepatocellular carcinoma. Death receptor-mediated apoptosis is triggered when ligands TNF-a, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand bind their cognate death receptors TNFR1, DR4/ 5 and Fas, respectively, activating downstream death-inducing cell signaling cascades. The ligands for these receptors are expressed by cells of the immune system, TNF-a and TRAIL by cells of the innate immune system such as NK cells and macrophages, and Fas ligand by T-lymphocytes [5,6]. Modulation of hepatocyte apoptosis by death receptors, especially as mediated by inflammatory cells, is a potential therapeutic strategy for NASH, but has yet to be realized
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