Homocysteine enhances cell proliferation in hepatic myofibroblastic stellate cells

Homocysteine is an intermediate in sulfur amino acid metabolism, which takes place mainly in the liver. Recent studies have shown that hyperhomocysteinemia in patients and murine models develop hepatic fibrosis. To define mechanisms underlying homocysteine-induced hepatic fibrosis, the effect of hom...

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Bibliographic Details
Published in:Journal of molecular medicine (Berlin, Germany) Germany), 2009, Vol.87 (1), p.75-84
Main Authors: Zou, Cheng-Gang, Gao, Shun-Yu, Zhao, Yue-Shui, Li, Shu-De, Cao, Xiu-Zhen, Zhang, Yan, Zhang, Ke-Qin
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cell Proliferation - drug effects
General aspects
Hepatic Stellate Cells - metabolism
Homocysteine - blood
Homocysteine - pharmacology
Human Genetics
Hyperhomocysteinemia - blood
Internal Medicine
Liver Cirrhosis - blood
Male
Medical sciences
Molecular Medicine
NADPH Oxidases - metabolism
Original Article
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
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Summary:Homocysteine is an intermediate in sulfur amino acid metabolism, which takes place mainly in the liver. Recent studies have shown that hyperhomocysteinemia in patients and murine models develop hepatic fibrosis. To define mechanisms underlying homocysteine-induced hepatic fibrosis, the effect of homocysteine on hepatic stellate cell (HSC) proliferation was examined. In the present study, homocysteine promoted proliferation in myofibroblastic HSCs. Homocysteine elicited a transient formation of reactive oxygen species (ROS). The initial ROS activated extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which were involved in the activation of NAD(P)H oxidases and the generation of more ROS. The activation of NAD(P)H oxidases resulted from upregulation of the expression of p22 phox and the phosphorylation of p47 phox . The ROS derived from NAD(P)H oxidases activated the PI3K/Akt pathway, thus promoting cellular proliferation in HSCs. These findings provide a mechanistic explanation for the development and progression of hepatic fibrosis in hyperhomocysteinemia.
ISSN:0946-2716
1432-1440
DOI:10.1007/s00109-008-0407-2