THE C-TERMINAL PEPTIDE OF ALPHA-1-ANTITRYPSIN INCREASES LOW-DENSITY-LIPOPROTEIN BINDING IN HEPG2 CELLS

Hydrophobic fragments generated from various proteolytically degraded precursor proteins are known to form amyloid fibrils which have biolog ical effects unrelated to precursor function. We examined the effects on HepG2 cells of the fibrillar and soluble C-terminal peptide [AAT-(3 58-394)] generated during the cleavage of the alpha-l-antitrypsin mole cule by target proteinase. Soluble and fibrillar forms of AAT(358-394) -peptide increased low-density lipoprotein (LDL) binding by 1-fold and 15-fold, respectively, an effect which was diminished by incubation o r coincubation of cells with LDL, but was not affected by the serpin-e nzyme complex. This effect of AAT-(358-394)-peptide appears to be on L DL receptor binding and not on the serpin-enzyme complex (SEC) or LDL receptor-related protein binding. The terminal deoxynucleotidyl transf erase-biotin dUTP nick-end labeling assay for apoptosis showed increas ed DNA fragmentation in cells incubated with AAT-(358-394)-peptide fib rils relative to controls and LDL-incubated cells. [H-3]Thymidine inco rporation in cells incubated with fibrils for 4 days decreased by 60%. We conclude that interaction of AAT-(358-394)-peptide fibrils with ce ll surface receptor(s) disturbs intracellular cholesterol homeostasis and induces cell death.