Hepatic fat-storing cells (FSC) play a key role in the development of
fibrosis as a major source of
collagen and other extracellular matrix (ECM)
proteins in the injured liver. Both experimental and clinical studies have shown that lipid peroxidation is often associated with the development of
liver fibrosis. Here we report that exposure of cultured human liver FSC to the
pro-oxidant system ascorbate/
iron results in an early induction of lipid peroxidation, as monitored in terms of MDA and fluorescent
aldehyde/
protein adducts production, and in a significant increase of the constitutive expression of
procollagen type I mRNA paralleled by the accumulation of the
protein in cell
culture media. This fibrogenic effect is almost completely abolished by pretreatment of FSC cultures with the
antioxidants alpha-tocopherol (
Vitamin E) or diphenylphenylendiamine (
DPPD). Moreover, treatment of FSC with 1.0 microM
4-hydroxynonenal (HNE), a highly reactive aldehydic end-product of lipid peroxidation, results in a significant stimulation of
procollagen type I gene expression and synthesis, suggesting that this
aldehyde also exerts profibrogenic activity. These findings indicate that oxidative reactions can directly influence
procollagen I gene expression and synthesis in FSC, thus contributing to the development of
liver fibrosis.