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.