OVEREXPRESSION OF APOLIPOPROTEIN-E PREVENTS DEVELOPMENT OF DIABETIC HYPERLIPIDEMIA IN TRANSGENIC MICE

To determine the role of apolipoprotein E (apoE) in diabetic hyperlipi demia, we induced diabetes in transgenic mice overexpressing apoE by i ntravenons injection of streptozotocin (STZ) and examined plasma lipop rotein metabolism in these mice. In STZ-induced diabetic mice, blood g lucose levels were >19 mmol/l (350 mg/dl) and plasma insulin levels we re reduced to <5 pmol/l (1 mu U/ml). The diabetic nontransgenic mice d eveloped hypercholesterolemia (plasma total cholesterol level: 4.55 +/ - 1.32 vs. 1.97 +/- 0.13 mmol/l [176 +/- 51 vs. 76 +/- 5 mg/dl]) and h ypertriglyceridemia (plasma triglyceride level: 0.82 +/- 0.29 vs, 0.42 +/- 0.11 mmol/l [73 +/- 26 vs. 37 +/- 10 mg/dl]) compared with values before induction of diabetes, In the diabetic nontransgenic mice, enh anced intestinal acyl-CoA:cholesterol acyltransferase activity was dem onstrated, a factor that may contribute to the development of diabetic hyperlipidemia. Induction of apoE remarkably reduced the development of hyperlipidemia in diabetic transgenic mice compared with diabetic n ontransgenic mice (plasma cholesterol level: 4.55 +/- 1.32 vs. 3.31 +/ - 0.47 mmol/l [176 +/- 51 vs. 128 +/- 18 mg/dl], P < 0.01, and plasma triglyceride level: 0.82 +/- 0.29 vs. 0.17 +/- 0.11 mmol/l [73 +/- 26 vs. 15 +/- 10 mg/dl], P < 0.01). plasma Lipoprotein analysis by gel fi ltration chromatography showed that the reduction of plasma cholestero l and triglyceride levels was due to the disappearance of lipoproteins containing apoB. In these studies, we demonstrated the usefulness of STZ-induced diabetes in mice as an animal model for diabetic hyperlipi demia and demonstrated that endogenous induction of apoE in transgenic mice improved diabetic hyperlipidemia.