Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.
Published
Journal Article
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.
Full Text
Duke Authors
- Abdelmalek, Manal F.
- Choi, Steven Sok
- Diehl, Anna Mae
- Guy, Cynthia Dianne
- Kuo, Paul C.
- Moylan, Cynthia Ann
- Schroder, Vanessa Teaberry
Cited Authors
- 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
Published Date
- January 2011
Published In
Volume / Issue
- 53 / 1
Start / End Page
- 106 - 115
PubMed ID
- 20967826
Pubmed Central ID
- 20967826
Electronic International Standard Serial Number (EISSN)
- 1527-3350
Digital Object Identifier (DOI)
- 10.1002/hep.23998
Language
- eng
Conference Location
- United States