Abstract
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.
Highlights
Contrary to normal rats, diabetic rats are known to develop marked hypercholesterolemia when fed a cholesterolenriched diet
In the present study we used short term diabetic rats, i.e., during the 3 days following streptozotocin injection, to demonstrate the role of the intestinal acyl-CoA:cholesterol acyltransferase (ACAT) in the induction of the diabetes-linked hypercholesterolemia independently of intestinal hypertrophy or hyperphagia which are factors implicated in the hyperresponse of diabetic rats to cholesterol feeding [18,19,20]
Our results show that hyperphagia and intestinal hypertrophy can be excluded as triggering factors for the hyperresponsiveness of diabetic rats to cholesterol feeding
Summary
Diabetic rats are known to develop marked hypercholesterolemia when fed a cholesterolenriched diet. As observed in the previous experiment (Table 2), diabetic rats fed a high-fat diet for 3 days displayed a marked increase in plasma cholesterol levels compared to normal rats (176 f 30 vs 74 f 6 mg/dl, P < 0.01). The elevated liver free cholesterol, cholesteryl ester, and triglyceride levels in the diabetic rats were significantly reduced to the range measured in nondiabetic rats after treatment with CL-277082.
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