Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytes: a new role for homocysteine in liver fibrosis

Elevated plasma levels of homocysteine have been shown to interfere with no rmal cell function in a variety of tissues and organs, such as the vascular wall and the liver. However, the molecular mechanisms behind homocysteine effects are not completely understood. In order to better characterize the cellular effects of homocysteine, eve have searched for changes in gene exp ression induced by this amino acid. Our results show that homocysteine is a ble to induce the expression and synthesis of the tissue inhibitor of metal loproteinases-1 (TIMP-1) in a variety of cell types ranging from vascular s mooth muscle cells to hepatocytes, HepG2 cells and hepatic stellate cells. In this latter cell type, homocysteine also stimulated al(I) procollagen mR NA expression. TIMP-1 induction by homocysteine appears to be mediated by i ts thiol group. Additionally, we demonstrate that homocysteine is able to p romote activating protein-1 (AP-I) binding activity, which has been shown t o be critical for TIMP-1 induction. Our findings suggest that homocysteine may alter extracellular matric. homeostasis on diverse tissular backgrounds besides the vascular wall. The liver could be considered as another target for such action of homocysteine. Consequently, the elevated plasma levels of this amino acid found in different pathological or nutritional circumsta nces may cooperate with other agents, such as ethanol, in the onset of live r fibrosis. (C) 1999 Elsevier Science B.V. All rights reserved.