Abstract
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 p22phox and the phosphorylation of p47phox. 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.
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Acknowledgements
This work was supported by a grant (2007CB411600) from the National Basic Research Program of China (973 Program; to K-Q Z), a grant (30560036) from the National Natural Science Foundation of China (to C-G Z), and a grant (2006-33) from the Scientific Research Foundation for Returned Scholars, Ministry of Education of China (to C-G Z). We thank Dr. L-M Xu (Shanghai University of CTM) for the generous gift of HSC-T6 cells.
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Cheng-Gang Zou and Shun-Yu Gao contributed equally to this study.
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Figure S1
Homocysteine upregulates the protein levels of PCNA. HSCs were incubated with 100 μM homocysteine for 8 h. The protein levels were detected by Western blotting. The blot is representative of three independent experiments (DOC 37.5 KB)
Figure S2
Homocysteine promotes proliferation in HSC-T6 cells. HSC-T6 cells were incubated with varying concentrations of homocysteine (Hcy) for 24 h. The cell proliferation was assessed by [3H]-thymidine incorporation into DNA. These results are means ± SD of five experiments. *P < 0.05 versus control (DOC 25.5 KB)
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Zou, CG., Gao, SY., Zhao, YS. et al. Homocysteine enhances cell proliferation in hepatic myofibroblastic stellate cells. J Mol Med 87, 75–84 (2009). https://doi.org/10.1007/s00109-008-0407-2
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DOI: https://doi.org/10.1007/s00109-008-0407-2