To determine how insulin deficiency leads to hypercholesterolemia, we examined cholesterol absorption, synthesis, and utilization in streptozocin-induced diabetic rats fed a grain-based diet ad libitum. Absorbed dietary cholesterol was determined from measurement of dietary cholesterol intake and previous data for cholesterol fractional absorption. Daily rates of cholesterol synthesis in the small intestine, liver, and periphery were calculated from recovery of labeled sterols after injection of 3H2O at six times during 24 h. Utilization of cholesterol for growth, fecal excretion, and bile acid synthesis were also determined. Absorbed dietary cholesterol in diabetic rats was double that in control rats. The contribution of absorbed cholesterol to total cholesterol production (sum of absorbed dietary cholesterol) and endogenous cholesterol synthesis) in control rats was 24% compared to 48% in diabetic rats. The increase in diabetic rats was due to overeating and, to a lesser extent, to increased fractional absorption. Overeating also induced intestinal hypertrophy and a twofold increase in cholesterol synthesis by the small intestine to 24% of whole-body production in diabetic rats. Consequently, the small intestine accounted for 72% of daily cholesterol input in diabetic rats compared to 37% in control rats, with diet accounting for two-thirds of the cholesterol input via the small intestine in both groups. In response to this increased input from the intestine, cholesterol synthesis in the periphery was 39% of whole-body production in control rats compared to 22% in diabetic rats, and synthesis in the liver was 26 and 6% of total cholesterol production in control and diabetic rats, respectively. The net effect of these changes was a decrease in whole-body synthesis equal to the increase in absorbed dietary cholesterol and no change in whole-body cholesterol production in diabetic rats. The need for cholesterol as substrate for bile acid synthesis was met largely by absorption from the diet in diabetic rats and by synthesis in the liver in control rats. The need for cholesterol in the periphery was entirely met by synthesis in situ in both groups. We conclude that 1) an increased fraction of the net cholesterol production is derived from intestinal sources and transported through the blood in diabetic rats, and 2) cholesterol absorbed from the diet contributes more to the hypercholesterolemia of diabetic rats than the increased cholesterol synthesis in the small intestine.

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