Importance of exogenous cholesterol in diabetic rats: effects of treatment with insulin or with an acyl-CoA:cholesterol acyltransferase inhibitor.

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.