PMID- 17058265
OWN - NLM
STAT- MEDLINE
DCOM- 20061130
LR  - 20171116
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 44
IP  - 5
DP  - 2006 Nov
TI  - Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and 
      fibrosis in mice.
PG  - 1267-77
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 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.
FAU - Choi, Steve S
AU  - Choi SS
AD  - Division of Gastroenterology and Department of Medicine, Duke University Medical 
      Center, Durham, NC, USA.
FAU - Sicklick, Jason K
AU  - Sicklick JK
FAU - Ma, Qi
AU  - Ma Q
FAU - Yang, Liu
AU  - Yang L
FAU - Huang, Jiawen
AU  - Huang J
FAU - Qi, Yi
AU  - Qi Y
FAU - Chen, Wei
AU  - Chen W
FAU - Li, Yin-Xiong
AU  - Li YX
FAU - Goldschmidt-Clermont, Pascal J
AU  - Goldschmidt-Clermont PJ
FAU - Diehl, Anna Mae
AU  - Diehl AM
LA  - eng
GR  - R01 AA010154/AA/NIAAA NIH HHS/United States
GR  - R01 AA012059/AA/NIAAA NIH HHS/United States
GR  - R01 DK053792/DK/NIDDK NIH HHS/United States
GR  - R01 HL071536/HL/NHLBI NIH HHS/United States
GR  - T32 DK007568/DK/NIDDK NIH HHS/United States
GR  - T32 DK007713/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Actins)
RN  - 0 (Neuropeptides)
RN  - 0 (Rac1 protein, mouse)
RN  - 0 (Reactive Oxygen Species)
RN  - 9007-34-5 (Collagen)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
RN  - EC 1.14.13.- (Cytochrome P-450 CYP2E1)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.6.5.2 (rac GTP-Binding Proteins)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Actins/genetics
MH  - Animals
MH  - Carbon Tetrachloride/adverse effects
MH  - Cells, Cultured
MH  - Collagen/analysis
MH  - Cytochrome P-450 CYP2E1/metabolism
MH  - Hepatocytes/*metabolism
MH  - Immunohistochemistry
MH  - Liver/*pathology
MH  - Liver Cirrhosis/metabolism
MH  - Liver Diseases/*metabolism/mortality/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - NADPH Oxidases/deficiency
MH  - Neuropeptides/*biosynthesis/genetics
MH  - Reactive Oxygen Species/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - rac GTP-Binding Proteins/*biosynthesis/genetics
MH  - rac1 GTP-Binding Protein
EDAT- 2006/10/24 09:00
MHDA- 2006/12/09 09:00
CRDT- 2006/10/24 09:00
PHST- 2006/10/24 09:00 [pubmed]
PHST- 2006/12/09 09:00 [medline]
PHST- 2006/10/24 09:00 [entrez]
AID - 10.1002/hep.21375 [doi]
PST - ppublish
SO  - Hepatology. 2006 Nov;44(5):1267-77. doi: 10.1002/hep.21375.