Postprandial
hyperlipidemia (PH) is recognized as a significant risk factor for
cardiovascular disease. The present study, involving rats with
streptozotocin (STZ)-induced diabetes, was performed to establish a PH model and to examine the relation between small intestinal
acyl-coenzyme A:
cholesterol acyltransferase (ACAT) activity and serum
lipid levels in the postprandial state. The small intestinal ACAT activities in normal rats during the experimental period were 4 to 5 pmol/mg
protein per minute. In contrast, in the diabetic rats, the ACAT activities were 2 to 3 times higher than activities seen in normal rats from 7 to 21 days after the STZ injection in the absence of a high fat diet and
hyperplasia in the gut. In an oral fat-loading test that used diabetic rats that had been injected with STZ (60 mg/kg) intravenously 14 days previously, the postloading changes in the serum concentrations of total
cholesterol (TC) and
triglyceride (TG) were significantly greater in the diabetic rats than in normal rats. Single
oral administration of (1s,2s)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]
cyclohexane- 1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1, 3-
dioxane-4-carbonyl)amino]
propionate (
F-1394, 3 to 30 mg/kg), a potent ACAT inhibitor, suppressed the post-fat-loading elevation of serum TC levels in the diabetic rats in a dose-dependent manner without affecting serum
glucose levels. Furthermore, the small intestinal ACAT activity, serum TG levels, and lymphatic absorption of TC and TG in the rats that were administered
F-1394 (30 mg/kg) were reduced by approximately 90%, 70%, 30%, and 15%, respectively. This is the first evidence that elevated ACAT activity in the gut, unlike
hyperplasia and
hyperphagia, induces PH in rats. Our results strongly suggest that
F-1394 may be a potential treatment for PH in humans.