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

Wing Kin Syn, Steve S. Choi, Evaggelia Liaskou, Gamze F. Karaca, Kolade M. Agboola, Ye Htun Oo, Zhiyong Mi, Thiago A. Pereira, Marzena Zdanowicz, Padmini Malladi, Yuping Chen, Cynthia Moylan, Youngmi Jung, Syamal D. Bhattacharya, Vanessa Teaberry, Alessia Omenetti, Manal F. Abdelmalek, Cynthia D. Guy, David H. Adams, Paul C. KuoGregory A. Michelotti, Peter F. Whitington, Anna Mae Diehl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

166 Scopus citations

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+/-) (overly active Hh signaling) mice, and OPN-deficient 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+/- 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.

Original languageEnglish (US)
Pages (from-to)106-115
Number of pages10
JournalHepatology
Volume53
Issue number1
DOIs
StatePublished - Jan 2011

ASJC Scopus subject areas

  • Hepatology

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