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Decreased lipoprotein clearance is responsible for increased cholesterol in streptozotocin treated LDL receptor knockout mice

Divisions of Preventive Medicine and Nutrition, and Cardiology; Columbia University, New York, NY

Objective: Patients with diabetes often have dyslipidemia and increased postprandial lipidemia. Induction of diabetes in LDL receptor (Ldlr–/–) knockout mice also leads to marked dyslipidemia. The reasons for this are unclear.

Research Design and Methods: We placed Ldlr–/– and heterozygous LDL receptor knockout (Ldlr+/–) mice on a high cholesterol (0.15%) diet, induced diabetes with streptozotocin (STZ), and assessed reasons for differences in plasma cholesterol.

Results: Diabetic Ldlr–/– mice had plasma cholesterol levels more than double those of non-diabetic controls. FPLC and ultracentrifugation showed an increase in both VLDL and LDL. Plasma VLDL became more cholesterol-enriched and both VLDL and LDL had a greater content of apoE. In LDL the ratio of apoB48 to apoB100 was increased. ApoB production, assessed using [³⁵S]methionine labeling in Triton WR1339-treated mice, was not increased in fasting diabetic mice. Similarly, postprandial lipoprotein production was not increased. Reduction of cholesterol in the diet to normalize the amount of cholesterol intake by the control and diabetic animals reduced plasma cholesterol levels in diabetic mice, but plasma cholesterol was still markedly elevated compared to non-diabetic controls. LDL from diabetic mice was cleared from the plasma and trapped more rapidly by livers of control mice. STZ-treatment reduced liver expression of the proteoglycan sulfation enzyme, Ndst1, an effect that was reproduced in cultured hepatocytyes by high glucose-containing medium.

Conclusion: Diabetic cholesterol-fed mice developed hyperlipidemia due to a non-LDL receptor defect in clearance of circulating apoB-containing lipoproteins.

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