The authors studied xanthomatous skin in
cholesterol-fed rabbits for changes in
lipid content and in activities of
enzymes regulating intracellular
lipid content. After 80 days of hypercholesterolemic diet,
xanthomas were widespread and changes in lipid metabolism were marked. In both tissue homogenates and cell membrane pellets, unesterified
cholesterol and
phospholipids increased 2-fold to 6-fold, and
cholesteryl esters increased about 30-fold. Tissue
triglycerides, however, decreased to half the levels found in control skin.
Cholesterol esterification rates, measured by activity of
acyl coenzyme A:
cholesterol acyltransferase, increased moderately to markedly;
hydrolase activity against
4-methylumbelliferyl oleate also increased at both
acid and neutral pH, but
hydrolase activity against
cholesterol oleate increased only at
acid pH. Thus,
hypercholesterolemia caused striking increases in intracellular
cholesterol esterification rates, increases in
lipase activity at both neutral and
acid pH, and increases in
cholesteryl ester hydrolase activity at
acid pH. Increases in
cholesterol-esterifying activity uniformly exceeded increases in
cholesteryl ester hydrolytic activity in congruence with net accumulation of
cholesteryl ester. Skin
xanthoma grade, however, had no consistent relation to the
cholesterol esterification rates. Instead, the
enzyme data suggested that marked abnormalities of lipid metabolism are diffusely distributed through dermal tissue as a precondition for the focal emergence of
xanthomas.