Overexpression of apolipoprotein E prevents development of diabetic hyperlipidemia in transgenic mice.

To determine the role of apolipoprotein E (apoE) in diabetic hyperlipidemia, we induced diabetes in transgenic mice overexpressing apoE by intravenous injection of streptozotocin (STZ) and examined plasma lipoprotein metabolism in these mice. In STZ-induced diabetic mice, blood glucose levels were > 19 mmol/l (350 mg/dl) and plasma insulin levels were reduced to < 5 pmol/l (1 microU/ml). The diabetic nontransgenic mice developed hypercholesterolemia (plasma total cholesterol level: 4.55 +/- 1.32 vs. 1.97 +/- 0.13 mmol/l [176 +/- 51 vs. 76 +/- 5 mg/dl]) and hypertriglyceridemia (plasma triglyceride level: 0.82 +/- 0.29 vx. 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, enhanced intestinal acylCoA:cholesterol acyltransferase activity was demonstrated, 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 nontransgenic 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 filtration chromatography showed that the reduction of plasma cholesterol 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 hyperlipidemia and demonstrated that endogenous induction of apoE in transgenic mice improved diabetic hyperlipidemia.