title: Decreased lipoprotein clearance is responsible for increased cholesterol in LDL receptor knockout mice with streptozotocin-induced diabetes.
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.
  
  
  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.
authors.affiliation: Division of Preventive Medicine, Columbia University, New York, New York 10032, USA. ijg3@columbia.edu
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Yunying
authors.initials: Y
authors.lastname: Hu
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Noh
authors.forename: Justin
authors.initials: J
authors.lastname: Wei
authors.forename: Lesley Ann
authors.initials: LA
authors.lastname: Huggins
authors.forename: Marnie G
authors.initials: MG
authors.lastname: Rackmill
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hamai
authors.forename: Brendan N
authors.initials: BN
authors.lastname: Reid
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
authors.forename: Li-Shin
authors.initials: LS
authors.lastname: Huang
mesh_terms: 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
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D001786:Blood Glucose; D002791:Cholesterol, Dietary; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol