ROLE OF LIVER EXTRACELLULAR-MATRIX IN TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF APOLIPOPROTEIN-A-I BY HEPATOCYTES

Apolipoprotein A-I, a protein produced mainly by hepatocytes, is of ma jor importance in prevention of atherosclerosis. Its serum level varie s according to the degree of liver fibrosis and the mechanism of this regulation is unknown. The aim of this study was to investigate the ro le of extracellular matrix in the regulation of apolipoprotein A-I by the liver. Primary mouse hepatocytes were cultured on different extrac ellular matrix components. The apolipoprotein A-I mRNA level was quant ified in these different culture conditions by a sensitive quantitativ e RT-PCR procedure and compared according to the extracellular matrix component used as substrate. A significant decrease in the apolipoprot ein A-I mRNA level was observed when cells were plated on fibronectin by comparison with cells cultured on all other components. Potential b inding of apolipoprotein A-I to the different matrix components was al so studied in vitro. We demonstrated that apolipoprotein A-I significa ntly bound to fibronectin in a concentration-dependent, saturable and specific manner. Thus, fibronectin, a major liver extracellular matrix component, can interact with apolipoprotein A-I both by downregulatin g its mRNA level in liver cells and by binding this molecule after its secretion in the extracellular space. Since fibronectin is the first matrix component to be produced in excess and deposited in liver fibro sis, it could be involved in the decrease in serum apolipoprotein A-I in alcoholic patients with liver fibrosis and cirrhosis.