Microscopy has played a critical role in first identifying
and then defining the role of lysosomes in formation of
atherosclerotic foam cells. We review the evidence implicating
lysosomal lipid accumulation as a factor in the pathogenesis
of atherosclerosis with reference to the role of microscopy.
In addition, we explore mechanisms by which lysosomal lipid
engorgement occurs. Low density lipoproteins which have become
modified are the major source of lipid for foam cell formation.
These altered lipoproteins are taken into the cell via
receptor-mediated endocytosis and delivered to lysosomes. Under
normal conditions, lipids from these lipoproteins are metabolized
and do not accumulate in lysosomes. In the atherosclerotic foam
cell, this normal metabolism is inhibited so that cholesterol
and cholesteryl esters accumulate in lysosomes. Studies of cultured
cells incubated with modified lipoproteins suggests this abnormal
metabolism occurs in two steps. Initially, hydrolysis of
lipoprotein cholesteryl esters occurs normally, but the resultant
free cholesterol cannot exit the lysosome. Further lysosomal
cholesterol accumulation inhibits hydrolysis, producing a mixture
of cholesterol and cholesteryl esters within swollen lysosomes.
Various lipoprotein modifications can produce this lysosomal
engorgement in vitro and it remains to be seen which
modifications are most important in vivo.