Variation in the human ApoB signal peptide modulates ApoB17 translocation

The functional effects of the common 27- or 24-amino-acid (aa) variants in the human apoB signal peptide (SP) on intracellular and secreted apoB17 wer e investigated in vitro. Only in the presence of oleate was a significant d ifference in intracellular and secreted SP27-B17 compared to SP24-B17 obser ved (P = 0.01 and P < 0.0007, respectively), although in the presence or ab sence of oleate mRNA levels from the two constructs were similar. After fra ctionation, oleate treatment enhanced microsomal SP27-B17 by 150% (P < 0.00 05) with a modest but significant effect on SP24-B17 (32% P = 0.007). Oleat e stimulated SP24-B17 accumulation in the nonmicrosomal fraction. The data suggest that the presence of oleate leads to inefficient translocation of t he 24-amino-acid signal peptide, possibly resulting in increased retrograde translocation into the cytoplasm and reduced intracellular and secreted le vels compared to the "wildtype" 27 aa SP. This implies a direct role of the SP variants in the regulation of apoB intracellular metabolism. (C) 2001 A cademic Press.