Abstract-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 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 Ϸ90%, 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. C oronary heart disease (CHD) resulting from premature atherosclerosis is a major cause of death in insulindependent and non-insulin-dependent diabetic patients. 1,2 Abnormalities in the metabolism of plasma lipoproteins and lipids in the postprandial state have been reported in diabetic patients, 3-9 and now evidence is being accumulated indicating that postprandial increases in triglyceride (TG)-rich lipoprotein, 10,11 which is known as one of the atherogenic remnant lipoproteins, 12,13 TG, 14,15 and cholesterol 16 remarkably contribute to the occurrence of CHD in such patients.A number of studies have reported that rats with streptozotocin (STZ)-induced diabetes (STZ-diabetic rats) shows severe hyperlipidemia after exogenous fat loading. [17][18][19] It has been suggested that the severe hyperlipidemia occurring in STZ-diabetic rats fed a high fat diet could be attributable to a marked increase in fat absorption via the gut, which in turn could be due to an abnormal increase in small intestinal acylcoenzyme A:cholesterol acyltransferase (ACAT) activity. 20 Indeed, repeated administration of an ACAT inhibitor, such as 21 CL-277082, 22,23 or FR 145237, 24 markedly decreases both the serum total cholesterol (TC) level and enhanced small intestinal ACAT activity in STZ-diabetic rats fed a high fat diet. However, previous investigators using diabetic mo...

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Glucagon-like peptide-1 (GLP-1) is an incretin peptide that plays a crucial role in lowering blood glucose levels and holds promise for treating type II diabetes. In this study, we synthesized GLP-1 derivatives that were conjugated with glycosaminoglycans (GAGs), i.e., chondroitin (CH) or heparosan (HPN), to address the major limitation in their clinical use of GLP-1, which is its short half-life in the body. After exploring a variety of CHs with different molecular sizes and heterobifunctional linkers having different alkyl chains, we obtained CH-conjugated GLP-1 derivatives that stayed in blood circulation much longer (T1/2 elim > 25 h) than unconjugated GLP-1 and showed blood glucose-lowering efficacy up to 120 h after subcutaneous injection in mice. By using the same optimized linker design, we eventually obtained a HPN-conjugated GLP-1 derivative with efficacy lasting 144 h. These results demonstrate that conjugation with GAG is a promising strategy for improving the duration of peptide drugs.

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