We have expressed a cDNA to human apolipoprotein E (apoE) in Saccharomyces 
cerevisiae. Secretion of apoE was achieved only by the use of a mutant (upc2) 
strain of yeast with the phenotype of enhanced uptake and intracellular 
esterification of exogenous cholesterol. Approximately 40 ng/ml apoE was 
secreted by upc2 mutants in the absence of media cholesterol. ApoE secretion was 
increased 2-3-fold upon the inclusion of cholesterol in the growth media. This 
response to exogenous cholesterol was not mediated at the transcriptional level, 
since apoE mRNA levels were constant under all culture conditions. Concomitant 
with the increase in secretion following cholesterol uptake by upc2 strains, 
approximately 5% of secreted apoE was associated with lipid; polar and non-polar 
lipids were detected in this lipoprotein fraction. Intracellular degradation of 
apoE in non-secreting strains of yeast was minimized by the presence of null 
mutations in both vacuolar proteases with non-specific activity (pep4) and a 
Golgi endopeptidase with specificity for paired basic residues (kex2). The 
approach of expressing human apolipoproteins in yeast may identify factors that 
mediate lipoprotein biosynthesis in higher cells. One such factor could be the 
mammalian equivalent of the gene product of UPC2.