Rats maintained on a high-fat diet supplemented with
propylthiouracil develop a
hypercholesterolemia, an increased serum level of
apolipoprotein (
apo) E, abnormal
very low density lipoproteins (VLDL) and
low density lipoproteins (
LDL), and a
fatty liver which contains
cholesterol ester as its major
lipid. The
fatty liver secretes
apoE into a recirculating perfusate at a significantly higher rate and produces
cholesterol ester-rich,
apoC-deficient VLDL with slower electrophoretic mobility than the
triacylglycerol-rich VLDL produced by perfused normal livers.
LDL, secreted in significant quantities by the perfused
fatty liver, but not by the normal liver, is also
cholesterol rich and contains
apoE as well as
apoB. The incorporation of [(3)H]
leucine into apoVLDL and apoLDL secreted by the livers of the hypercholesterolemic animals and the apoVLDL secreted by the normal liver corresponds to the pattern visualized when the
apoproteins are separated by
polyacrylamide gel electrophoresis. Similar patterns are noted when non-recirculating perfusates are studied. These results indicate that the
cholesterol ester-rich,
apoC-deficient VLDL and the
apoE-containing
LDL found in the serum of hypercholesterolemic rats are not solely catabolic remnants of VLDL and
chylomicrons but are secreted by the liver. Separation of the perfusate
lipoproteins by
agarose gel filtration revealed that most of the
apoE secreted by the livers of hypercholesterolemic rats is found in the VLDL and
LDL, whereas
apoE secreted by the normal livers is distributed equally between VLDL,
high density lipoproteins, and a low molecular weight fraction which corresponds to the virtually delipidated
apoprotein. Thus the distribution of
apoE among the
lipoprotein fractions may be related to the total amount of
cholesterol being transported in the circulation.