Contrary to normal rats, diabetic rats fed a
cholesterol-rich diet become markedly hyperlipidemic. We have previously reported [J
Lipid Res 1992; 33:1475-14841bd that the intestinal
acyl-CoA:cholesterol acyltransferase (ACAT) plays a major role in the initiation of diabetes-associated
hypercholesterolemia. In the present study, we have shown that within the 3 days following diabetes induction by
streptozotocin, diabetic rats responded to
dietary cholesterol in a dose-dependent manner and their livers developed a large capacity to store
cholesteryl esters (up to 10.6 +/- 1.4 mg/g tissue). We also examined the effects of treatments with
insulin or with the ACAT inhibitor
CL-277082 on the uptake of exogenous [3H]-
cholesterol in 3-day diabetic rats. The amount of [3H]-
cholesterol in
chylomicrons was dramatically increased by the diabetic state (+110%; p < 0.01) reflecting a higher rate of
cholesterol absorption compared to normal rats. This change was dependent on the ACAT activity since the
CL-277082 treatment largely prevented the appearance of [3H]-
cholesterol in
chylomicrons (-88%; p < 0.001), and as a consequence in the other
lipoprotein classes.
Insulin treatment reduced only by 35% (p < 0.05) the [3H]-
cholesterol in
chylomicrons compared to the diabetic control rats, and failed to normalize the resulting
lipoprotein profile. These results indicate that as early as 3 days after diabetes induction, diabetic rats are highly sensitive to
dietary cholesterol concentrations, and that
insulin deficiency is not the sole factor involved in the
cholesterol hyperabsorption, which was totally suppressed by the ACAT inhibitor treatment.