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 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.
Zou
Cheng-Gang
CG
Laboratory for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, 650091, China.
Gao
Shun-Yu
SY
Zhao
Yue-Shui
YS
Li
Shu-De
SD
Cao
Xiu-Zhen
XZ
Zhang
Yan
Y
Zhang
Ke-Qin
KQ
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000097:blood; D008103:Liver Cirrhosis / Q000097:blood; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D006710:Homocysteine; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C515768:Cyba protein, rat; C060505:neutrophil cytosolic factor 1