Contrary to normal rats, diabetic rats are known to develop marked
hypercholesterolemia when fed a
cholesterol-enriched diet. The triggering factor involved in this hyperresponse has not been identified. With the aim of clarifying the role of the intestinal
acyl-CoA:cholesterol acyltransferase (ACAT), we studied the effects of a high fat diet and the changes of intestinal ACAT activity during the early development of
streptozotocin-diabetes in rats. Feeding diabetic rats with a diet enriched in
cholesterol and saturated fat produced an increase in plasma and in tissue
cholesterol as early as 3 days after
streptozotocin injection in the absence of
hyperphagia. Under these experimental conditions, treatment with
insulin or with the ACAT inhibitor
CL-277082 significantly reduced the plasma
cholesterol to levels measured in nondiabetic rats fed the same high fat diet. An increase in [14C]
cholesterol in plasma
very low density lipoprotein was observed after
oral administration of labeled
cholesterol to 3-day diabetic rats. In parallel experiments, the direct measurement of small intestine microsomal ACAT activity revealed an increase, averaging 288% in diabetic rats 3 days after diabetes induction. This change in ACAT activity occurred simultaneously with an increase in plasma
glucagon and was normalized by
insulin treatment. The induction of intestinal ACAT activity in diabetic rats, its modulation by
insulin, and the hypocholesterolemic effects of
insulin or
CL-277082 treatment clearly indicate that ACAT activity plays a major role in the initiation of diabetes-associated
hypercholesterolemia.