Effect of Hypocholesterolemia on Cholesterol Synthesis in Small Intestine of Diabetic Rats

Studies by our and other laboratories have demonstrated that cholesterol synthesis is increased in the small intestine of insulinopenic diabetic animals. In normal animals, many factors have been shown to regulate cholesterol synthesis in the small intestine, including changes in plasma cholesterol levels. The purpose of this study was to determine the effect of lowering plasma cholesterol levels on small intestine cholesterol synthesis in streptozocin-induced diabetic rats. In diabetic rats, 4-aminopyrazolo[3,4-d]pyrimidine (4-APP)-induced hypocholesterolemia (plasma cholesterol levels 20 mg/dl) resulted in a 2.5-fold increase in small intestine cholesterol synthesis, which was most marked in the distal small intestine, decreasing proximally. In the distal small intestine the incorporation of ³H₂O into cholesterol was 0.28 ± 0.04 μmol · h⁻¹ · g⁻¹ in diabetic rats versus 1.60 ± 0.38 in diabetic rats administered 4-APP (P < .01). This stimulation of cholesterol synthesis occurred in the upper villus, middle villus, and crypt cells isolated from the middle intestine of the 4-APP-treated diabetic animals. In agreement with these observations, “functional hypocholesterolemia” due to Triton WR-1339 administration also stimulated cholesterol synthesis 2.5-fold in the small intestine of normal and diabetic animals. In the distal small intestine, cholesterol synthesis was 0.43 ± 0.10 μmol · h⁻¹ · g⁻¹ in the diabetic rats versus 1.08 ± 0.21 in diabetic rats treated with Triton WR-1339 (P < .05). In both the 4-APP and Triton WR-1339 experiments, the response of the diabetic rats was similar to that observed in normal rats. Moreover, cholesterol administered orally could prevent the Triton WR-1339-induced increase in small intestine cholesterol synthesis, indicating that providing cholesterol via an alternate route (i.e., intraluminal) can block the increase in synthesis. The results reported in this article, together with our earlier observations demonstrating that luminal factors regulate cholesterol synthesis, indicate that small intestine cholesterol synthesis in diabetic animals is regulated by both luminal and circulating factors in the expected fashion.