| Summary: | 碩士 === 長庚大學 === 生物醫學研究所 === 97 === Many studies have strongly suggested that diabetes mellitus (DM) may accelerate atherosclerosis, the underlying mechanism of cardiovascular disease (CVD). Strong evidence also supports that LDL oxidation, endothelial dysfunction, and inflammations are involved in the pathogenesis of atherosclerosis. To better understand the contribution and interaction of the multiple risk factors in diabetes-accelerated atherosclerosis, apolipoprotein E-deficient (apoE-/-) mice (a spontaneous atherosclerosis animal model) treated with streptozotocin (STZ) were used as an animal model. This study also incorporated metabolomics as an approach to explore the trend and contribution of lipid disorders in diabetes-accelerated atherosclerosis. Proton-nuclear magnetic resonance (1H-NMR) spectroscopy was used as the tool for global lipid metabolite profiling in plasma and liver, whereas liquid chromatography-mass spectrometry (LC-MS) was used as a tool for global water-soluble metabolite profiling. Principal component analysis (PCA) and database (METLIN and Human Metabolome Database) search were used for finding candidate metabolites, which were significantly changed. Results demonstrated that lipid disorders causing by STZ-induced diabetes (type 1 DM) were more atherogenic (hypercholesterolemia). In DM group, plasma cholesterol, free fatty acids (FFAs), polyunsaturated fatty acids (PUFAs) and phosphatidylcholine (PC) were significantly elevated (P<0.05). Hepatic lipid metabolite profiling demonstrated that the lipid disorders shifted from high triacylglycerol (TG) in control group to high cholesterol in DM group. Liver was the major site where metabolic disturbance occurred. The highly positive correlations between cholesterol and PC in liver and plasma suggested that increased biosynthesis of cholesterol also stimulated the biosynthesis of PC in the liver. Water-soluble metabolite analysis by 1H-NMR demonstrated that lactate, alanine and acetate were significantly elevated (P<0.05) in the liver in DM group. This study concludes that the underlying mechanism in diabetes-accelerated atherosclerosis may be due to more severe and atherogenic lipid disorders in liver and plasma, namely from elevated TG to more atherogenic hypercholesterolemia. Elevation of plasma PC may be a potential biomarker to predict the progression of diabetes-accelerated atherosclerosis.
|
|---|
