Class A peptides inhibit atherosclerosis and protect cells from class L peptide-inediated lysis. Because the cytolytic process is concentration dependent, we hypothesized that at certain concentrations both classes of peptides exert similar effect(s) on cells. To test this hypothesis, we studied the effects of a class L peptide (18L = GIKKFLGSI-WKFIKAFVG) and a class A peptide, 18A-Pro-18A (18A = DWLKAFYDKVAEKLKEAF) (37pA), on apolipoprotein and lipoprotein production in HepG2 cells. Secretion of 35S-labeled apolipoprotein A-I (apoA-I) was stimulated by both 18L (110%) and 37pA (135%) at 10 and 20 nM of peptides, respectively. Both peptides enhanced the secretion of 3H-labeled phospholipids by 140% and 14C-labeled HDL-cholesterol (HDL-C) by 35% but had no significant effect on the total cholesterol mass or secretion. These results indicate that class L and class A peptides cause redistribution of cholesterol among lipoproteins in favor of HDL-C. Both peptides remodeled apoA-I-containing particles forming preβ- as well as α-HDL. This study suggests that increased secretion of phospholipids and apoA-I and the formation of preβ-HDL particles might contribute to the antiatherogenic properties of these peptides. Copyright © 2004 by the American Society for Biochemistry and Molecular Biology, Inc.