Recently, osteopontin (OPN) has been suggested as a target gene of Gli-1.6 Simultaneously with a proliferative response, a fibrogenic response occurs. Immature ductular cells and fibroblastic cells proliferate in parallel with bridging fibrosis as nonalcoholic

fatty PLX-4720 manufacturer liver disease progresses to cirrhosis.3 Hh signaling can induce epithelial-to-mesenchymal transition (EMT) responses in ductular-type progenitors that assume a myofibroblast phenotype.7 An EMT response occurs after exposure to transforming growth factor β (TGF-β), an inducer of Hh signaling.8 Hepatic stellate cells (HSC) are also responsive to Hh, which induces the activation of quiescent HSCs into myofibroblasts and maintains viability while inhibiting the apoptosis of HSCs and promoting proliferation.9 Leptin, a powerful profibrogenic cytokine, activates HSCs through the Hh ligand; this mechanism is dependent on PI3K/protein kinase B induction.10 OPN, a pleomorphic glycoprotein, mediates inflammation and carcinogenesis. Its expression is increased in the obese11 and correlates with insulin resistance and steatosis.12 OPN triggers fibrogenesis; this has been

demonstrated in vitro, in in vivo animal models, and in human liver diseases. HSC activation is associated with OPN up-regulation; additionally, HSC incubation GDC 973 with OPN induces proliferative and migratory effects as well as collagen production and TGF-β receptor up-regulation.13 In viral hepatitis, OPN correlates with fibrosis and the risk and severity of hepatic cirrhosis.14 Also, in NASH, OPN seems crucial to fibrogenesis. Rats fed a high-fat diet presented OPN up-regulation correlating with α-smooth muscle actin and fibrosis in steatotic livers.15 In the methionine choline–deficient Amrubicin (MCD) mice model, steatosis and fibrosis were correlated with OPN up-regulation.16 In OPN knockout mice, an MCD diet induced less hepatic inflammation and fibrosis. OPN has been linked to oval cell induction17 and hepatic carcinogenesis and is

associated with decreased survival in patients with hepatocellular carcinoma.18 In the January 2011 issue of HEPATOLOGY, Syn et al.19 report that OPN is a missing link between Hh signaling and fibrosis in NASH. In the first stage, they fed an MCD diet to wild-type mice and two sets of knockout mice: Ptc+/− mice partially deficient in Ptc with overly inducible Hh signaling and OPN−/− mice deficient in OPN. Ptc+/− mice developed more severe fibrosis that was associated with greater increases in OPN in comparison with wild-type mice. In contrast, OPN−/− mice developed significantly less fibrosis, despite similar Hh induction, according to Gli-2 staining. In the second stage, they cultured HSCs with S-antigen (an Hh agonist) and cyclopamine (an Hh antagonist). In HSCs, OPN production was increased by Hh agonists and decreased by antagonists, and this demonstrated that OPN production was dependent on Hh signaling.