Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding osteopontin (OPN), a profibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesize that Hh signaling induces OPN to promote liver fibrosis in NASH. Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc 1/2 ) (overly active Hh signaling) mice, and OPNdeficient mice before and after feeding methionine and choline-deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and nondiseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSCs) were cultured in medium with different OPN activities to determine effects on HSC phenotype. When fed MCD diets, Ptc 1/2 mice expressed more OPN and developed worse liver fibrosis (P < 0.05) than WT mice, whereas OPN-deficient mice exhibited reduced fibrosis (P < 0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSCs, SAG (an Hh agonist) up-regulated, whereas cyclopamine (an Hh antagonist) repressed OPN expression (P < 0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSCs (P < 0.05); neutralizing OPN with RNA aptamers attenuated this (P < 0.05). Conclusion: OPN is Hh-regulated and directly promotes profibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis stage. Therefore, OPN inhibition may be beneficial in NASH (HEPATOLOGY 2011;53:106-115) N onalcoholic steatohepatitis (NASH) is a potentially serious form of chronic liver injury because it increases the risk of developing cirrhosis and primary liver cancer. The mechanisms that lead to these outcomes have not been fully elucidated, but they appear to involve responses triggered

Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model

“…OPN has recently been described as being induced by hedgehog (Hh) signaling, and to promote fibrogenesis in NASH-related cirrhosis. 45 As in 1-week DDC-treated mice OPN þ granules appear in zone 1 hepatocytes further studies on the relationship between keratin integrity and Hh signaling in acute liver toxicity will be needed. However, as in chronically DDC-intoxicated animals OPN þ hepatocytes decrease in number or even disappear irrespective of the K status chronically induced K alterations do not seem to be linked to OPN.…”

Intracellular Osteopontin Inhibits Toll-like Receptor Signaling and Impedes Liver Carcinogenesis

“…In liver, OPN is related to steatohepatitis (7), liver fibrosis progression (8), and liver cancer. In patients with HCC, elevated plasma OPN level is closely related to liver function deterioration and has a positive correlation to tumor stage.…”

Pentoxifylline inhibits liver fibrosis via hedgehog signaling pathway

“…Activation of this signaling pathway promotes quiescent HSCs differentiation, proliferation and suppresses apoptosis [22,24] . HSCs proliferate and differentiate when the expression of related genes of HH signaling pathway was up-regulated; conversely, HSCs become apoptosis [25,26] . HSC activation is the central link of liver fibrosis [27][28][29] .…”