Decreased lipoprotein clearance is responsible for increased cholesterol in LDL
receptor knockout mice with streptozotocin-induced diabetes.
Authors Goldberg IJ, Hu Y, Noh HL, Wei J, Huggins LA, Rackmill MG, Hamai H, Reid BN,
Blaner WS, Huang LS
Submitted By Ira Goldberg on 2/8/2009
Status Published
Journal Diabetes
Year 2008
Date Published 6/1/2008
Volume : Pages 57(6) : 1674 - 1682
PubMed Reference 18346984
Abstract OBJECTIVE: Patients with diabetes often have dyslipidemia and increased
postprandial lipidmia. 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: STZ-induced diabetic Ldlr(-/-) mice had plasma
cholesterol levels more than double those of nondiabetic controls.
Fast-performance liquid chromatography 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 apolipoprotein (apo)E. In LDL the
ratio of apoB48 to apoB100 was increased. ApoB production, assessed using
[(35)S]methionine labeling in Triton WR1339-treated mice, was not increased in
fasting STZ-induced 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 STZ-induced diabetic animals
reduced plasma cholesterol levels in STZ-induced diabetic mice, but plasma
cholesterol was still markedly elevated compared with nondiabetic controls. LDL
from STZ-induced 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, heparan sulfate
N-deacetylase/N-sulfotrasferase-1, an effect that was reproduced in cultured
hepatocytyes by a high glucose-containing medium. CONCLUSIONS: STZ-induced
diabetic, cholesterol-fed mice developed hyperlipidemia due to a non-LDL
receptor defect in clearance of circulating apoB-containing lipoproteins.

Investigators with authorship
Ira GoldbergNew York University School of Medicine


Apobapolipoprotein B
Ldlrlow density lipoprotein receptor