Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice.
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 alpha-smooth muscle actin (alpha-sma) promoter, because alpha-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 CCl(4)-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.
Choi
Steve S
SS
Division of Gastroenterology and Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Sicklick
Jason K
JK
Ma
Qi
Q
Yang
Liu
L
Huang
Jiawen
J
Qi
Yi
Y
Chen
Wei
W
Li
Yin-Xiong
YX
Goldschmidt-Clermont
Pascal J
PJ
Diehl
Anna Mae
AM
D000199:Actins / Q000235:genetics; D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000172:deficiency; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020744:rac GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D020830:rac1 GTP-Binding Protein
D000199:Actins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D003094:Collagen; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D019255:NADPH Oxidases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein