Abstract
Remnant lipoprotein levels elevate in plasma of diabetic patients, which is thought to be related to the occurrence and the development of atherosclerosis in diabetes. Our earlier report indicated streptozotocin-induced diabetic rats showed a marked hyperlipoproteinemia with the accumulation of chylomicron remnants after an exogenous cholesterol load. In order to clarify the mechanism of remnant accumulation in diabetes, we investigated post heparin lipolytic activity and hepatic lipoprotein receptors. However, elevated levels of remnant lipoproteins in diabetes could not be explained only by the impairments of either lipolysis or lipoprotein catabolism mediated through hepatic receptors. Then we investigated acyl CoA: cholesterol acyltransferase (ACAT) activity of absorptive epithelium in small intestine, which was reported to be one of regulating enzymes of intestinal cholesterol absorption. Streptozotocininduced diabetic rats were all given an equal amount of feed (20g/day) for 3 weeks. After a 24 hour fasting absorptive epithelium in small intestine of each rats was prepared and microsomal ACAT activity was measured in three groups; control group, diabetes mellitus (DM) group and cholesterol (chol)-fed DM group. ACAT activity in DM group was 4 times higher than that in control group (non-diabetic rats). There was no significant difference in ACAT activities between DM and chol-fed DM group. No significant difference was observed among 3 groups in microsomal levels of free cholesterol, which was used as substrate in measuring ACAT activity. Furthermore, in order to study the effect of melinamide, an inhibitor of ACAT, plasma lipoprotein levels after a 24 hour fasting were investigated in 3 groups; DM group, chol-fed DM group and melinamide-treated group. Cholesterol levels in melinamide treated group were lower than those in chol-fed DM group (p<0.01), and were higher than those in DM group (p<0.01). Triglyceride levels showed no significant difference among 3 groups. Lipoprotein analysis indicated that cholesterol levels in VLDL and IDL in melinamide-treated group were markedly lower than those in chol-fed DM group (p<0.05). In conclusion diabetic rats have elevated activity of intestinal ACAT and it may be a cause of remnant accumulation in cholesterol fed diabetic rats. Besides, it was confirmed that melinamide, an inhibitor of cholesterol absorption, is a effective drug for hyperlipidemia in diabetes mellitus.
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