Skip to main content
Journal cover image

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

Publication ,  Journal Article
Syn, W-K; Choi, SS; Liaskou, E; Karaca, GF; Agboola, KM; Oo, YH; Mi, Z; Pereira, TA; Zdanowicz, M; Malladi, P; Chen, Y; Moylan, C; Jung, Y ...
Published in: Hepatology
January 2011

UNLABELLED: 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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

January 2011

Volume

53

Issue

1

Start / End Page

106 / 115

Location

United States

Related Subject Headings

  • Veratrum Alkaloids
  • Up-Regulation
  • Osteopontin
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Mice
  • Methionine
  • Liver Cirrhosis
  • Humans
  • Hepatic Stellate Cells
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Syn, W.-K., Choi, S. S., Liaskou, E., Karaca, G. F., Agboola, K. M., Oo, Y. H., … Diehl, A. M. (2011). Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology, 53(1), 106–115. https://doi.org/10.1002/hep.23998
Syn, Wing-Kin, Steve S. Choi, Evaggelia Liaskou, Gamze F. Karaca, Kolade M. Agboola, Ye Htun Oo, Zhiyong Mi, et al. “Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.Hepatology 53, no. 1 (January 2011): 106–15. https://doi.org/10.1002/hep.23998.
Syn W-K, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology. 2011 Jan;53(1):106–15.
Syn, Wing-Kin, et al. “Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.Hepatology, vol. 53, no. 1, Jan. 2011, pp. 106–15. Pubmed, doi:10.1002/hep.23998.
Syn W-K, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, Mi Z, Pereira TA, Zdanowicz M, Malladi P, Chen Y, Moylan C, Jung Y, Bhattacharya SD, Teaberry V, Omenetti A, Abdelmalek MF, Guy CD, Adams DH, Kuo PC, Michelotti GA, Whitington PF, Diehl AM. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology. 2011 Jan;53(1):106–115.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

January 2011

Volume

53

Issue

1

Start / End Page

106 / 115

Location

United States

Related Subject Headings

  • Veratrum Alkaloids
  • Up-Regulation
  • Osteopontin
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Mice
  • Methionine
  • Liver Cirrhosis
  • Humans
  • Hepatic Stellate Cells