Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice

Steve S. Choi, Jason K. Sicklick, Qi Ma, Liu Yang, Jiawen Huang, Yi Qi, Wei Chen, Yin Xiong Li, Pascal J. Goldschmidt-Clermont, Anna Mae Diehl

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Rac, a small, GTP-binding protein in the Rho family, regulates several cellular functions, including the activation of NADPH oxidase, a major intracellular producer of reactive oxygen species (ROS). Hepatic stellate cells (HSCs) isolated from mice that are genetically deficient in NADPH oxidase produce less ROS, and their activation during chronic liver injury is abrogated, resulting in decreased liver fibrosis. Therefore, we hypothesized that HSC ROS production and activation would be enhanced, and fibrosis worsened, by increasing Rac expression in HSCs. To achieve this, we used transgenic mice that express constitutively active human Rac1 under the control of the α-smooth muscle actin (α-sma) promoter, because α-sma expression is induced spontaneously during HSC activation. Transgene expression was upregulated progressively during culture of primary Rac-transgenic HSCs, and this increased HSC ROS production as well as expression of activation markers and collagen. Similarly, Rac mice treated with carbon tetrachloride (CCl 4) accumulated greater numbers of activated HSCs and had more liver damage, hepatocyte apoptosis, and liver fibrosis - as well as higher mortality - than CCl4-treated wild-type mice. In conclusion, sustained activation of Rac in HSCs perpetuates their activation and exacerbates toxin-induced liver injury and fibrosis, prompting speculation that Rac may be a therapeutic target in patients with cirrhosis.

Original languageEnglish (US)
Pages (from-to)1267-1277
Number of pages11
JournalHepatology
Volume44
Issue number5
DOIs
StatePublished - Nov 1 2006

ASJC Scopus subject areas

  • Hepatology

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    Choi, S. S., Sicklick, J. K., Ma, Q., Yang, L., Huang, J., Qi, Y., Chen, W., Li, Y. X., Goldschmidt-Clermont, P. J., & Diehl, A. M. (2006). Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice. Hepatology, 44(5), 1267-1277. https://doi.org/10.1002/hep.21375