Decreased lipoprotein clearance is responsible for increased cholesterol in LDL receptor knockout mice with streptozotocin-induced diabetes.
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.


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.
Goldberg
Ira J
IJ
Division of Preventive Medicine, Columbia University, New York, New York 10032, USA. ijg3@columbia.edu
Hu
Yunying
Y
Noh
Hye-Lim
HL
Wei
Justin
J
Huggins
Lesley Ann
LA
Rackmill
Marnie G
MG
Hamai
Hiroko
H
Reid
Brendan N
BN
Blaner
William S
WS
Huang
Li-Shin
LS
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D001057:Apolipoproteins E / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000503:physiopathology; D050171:Dyslipidemias / Q000235:genetics; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000503:physiopathology; D008113:Liver Neoplasms; D008114:Liver Neoplasms, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency*; D014280:Triglycerides / Q000097:blood*; D014407:Tumor Cells, Cultured
D001055:Apolipoproteins B; D001057:Apolipoproteins E; D001786:Blood Glucose; D002791:Cholesterol, Dietary; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol