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Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells.

Publication ,  Journal Article
Choi, SS; Witek, RP; Yang, L; Omenetti, A; Syn, W-K; Moylan, CA; Jung, Y; Karaca, GF; Teaberry, VS; Pereira, TA; Wang, J; Ren, X-R; Diehl, AM
Published in: Hepatology
July 2010

UNLABELLED: Hepatic accumulation of myofibroblastic hepatic stellate cells (MF-HSCs) is pivotal in the pathogenesis of cirrhosis. Two events are necessary for MF-HSCs to accumulate in damaged livers: transition of resident, quiescent hepatic stellate cells (Q-HSCs) to MF-HSCs and expansion of MF-HSC numbers through increased proliferation and/or reduced apoptosis. In this study, we identified two novel mediators of MF-HSC accumulation: Ras-related C3 botulinum toxin substrate 1 (Rac1) and Hedgehog (Hh). It is unclear whether Rac1 and Hh interact to regulate the accumulation of MF-HSCs. We evaluated the hypothesis that Rac1 promotes activation of the Hh pathway, thereby stimulating signals that promote transition of Q-HSCs into MF-HSCs and enhance the viability of MF-HSCs. Using both in vitro and in vivo model systems, Rac1 activity was manipulated through adenoviral vector-mediated delivery of constitutively active or dominant-negative rac1. Rac1-transgenic mice with targeted myofibroblast expression of a mutated human rac1 transgene that produces constitutively active Rac1 were also examined. Results in all models demonstrated that activating Rac1 in HSC enhanced Hh signaling, promoted acquisition/maintenance of the MF-HSC phenotype, increased MF-HSC viability, and exacerbated fibrogenesis. Conversely, inhibiting Rac1 with dominant-negative rac1 reversed these effects in all systems examined. Pharmacologic manipulation of Hh signaling demonstrated that profibrogenic actions of Rac1 were mediated by its ability to activate Hh pathway-dependent mechanisms that stimulated myofibroblastic transition of HSCs and enhanced MF-HSC viability. CONCLUSION: These findings demonstrate that interactions between Rac1 and the Hh pathway control the size of MF-HSC populations and have important implications for the pathogenesis of cirrhosis.

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

July 2010

Volume

52

Issue

1

Start / End Page

278 / 290

Location

United States

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Rats, Sprague-Dawley
  • Rats
  • Phenotype
  • Male
  • Liver Cirrhosis
  • Humans
  • Hepatic Stellate Cells
  • Hedgehog Proteins
  • Gene Expression Regulation
 

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Choi, S. S., Witek, R. P., Yang, L., Omenetti, A., Syn, W.-K., Moylan, C. A., … Diehl, A. M. (2010). Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells. Hepatology, 52(1), 278–290. https://doi.org/10.1002/hep.23649
Choi, Steve S., Rafal P. Witek, Liu Yang, Alessia Omenetti, Wing-Kin Syn, Cynthia A. Moylan, Youngmi Jung, et al. “Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells.Hepatology 52, no. 1 (July 2010): 278–90. https://doi.org/10.1002/hep.23649.
Choi SS, Witek RP, Yang L, Omenetti A, Syn W-K, Moylan CA, et al. Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells. Hepatology. 2010 Jul;52(1):278–90.
Choi, Steve S., et al. “Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells.Hepatology, vol. 52, no. 1, July 2010, pp. 278–90. Pubmed, doi:10.1002/hep.23649.
Choi SS, Witek RP, Yang L, Omenetti A, Syn W-K, Moylan CA, Jung Y, Karaca GF, Teaberry VS, Pereira TA, Wang J, Ren X-R, Diehl AM. Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells. Hepatology. 2010 Jul;52(1):278–290.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

July 2010

Volume

52

Issue

1

Start / End Page

278 / 290

Location

United States

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Rats, Sprague-Dawley
  • Rats
  • Phenotype
  • Male
  • Liver Cirrhosis
  • Humans
  • Hepatic Stellate Cells
  • Hedgehog Proteins
  • Gene Expression Regulation