HUMAN APOLIPOPROTEIN-B SIGNAL SEQUENCE VARIANTS CONFER A SECRETION-DEFECTIVE PHENOTYPE WHEN EXPRESSED IN YEAST

Hyperlipidemia arises from a disturbance in the balance between produc tion and degradation of Lipoprotein particles. Variation in the secret ion of human apolipoprotein B (apoB), the major protein component of t riglyceride-rich lipoproteins, directly affects this homeostasis. Natu rally occurring apoB signal peptide variants (associated with hypertri glyceridemia, altered postprandial lipid metabolism, or atherosclerosi s) were investigated for their ability to direct transit through the s ecretion pathway. Three apoB signal peptide iso forms were fused to th e secretory protein, invertase, and expressed in yeast. A deletion or insertion in the hydrophobic core of the signal peptide mediated ineff icient translocation into the endoplasmic reticulum and was secretion- defective, relative to the common 27-residue isoform. Additionally, th e insertion apoB isoform was observed in yeast to confer a defect in e xport from the endoplasmic reticulum. Secretion of the apoB signal pep tide-invertase fusions responded positively to an inhibitor of calpain type I proteases. These observations suggest that the apoB signal pep tide plays a role in determining the levels of apoB degradation and se cretion and, thus, hyperlipidemia.