Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen α1 (I) gene expression in human liver fat-storing cells

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 α-tocopherol (Vitamin E) or diphenylphenylendiamine (DPPD). Moreover, treatment of FSC with 1.0 βM 4-hydroxynonenal (HNE), a high reactive aldehydic endproduct 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.