TY - JOUR
T1 - Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice
AU - Choi, Steve S.
AU - Sicklick, Jason K.
AU - Ma, Qi
AU - Yang, Liu
AU - Huang, Jiawen
AU - Qi, Yi
AU - Chen, Wei
AU - Li, Yin Xiong
AU - Goldschmidt-Clermont, Pascal J.
AU - Diehl, Anna Mae
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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.
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U2 - 10.1002/hep.21375
DO - 10.1002/hep.21375
M3 - Article
C2 - 17058265
AN - SCOPUS:33751003841
VL - 44
SP - 1267
EP - 1277
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 5
ER -