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Cytotoxicity of lipid-free apolipoprotein B
Authors:Shin-ya Morita  Eriko Takata  Tetsurou Handa
Institution:a Laboratory of Pharmaceutical Technology, Kobe Pharmaceutical University, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
b Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Abstract:To investigate the effect of apolipoprotein B (apoB) on cell viability, we used lipid-free apoB as a model for denatured apoB. Lipid-free apoB had cytotoxicity to J774 macrophages, CHO cells and HepG2 cells, whereas apoB bound to low density lipoprotein (LDL) and lipid-free apolipoprotein A-I had no effect on cell viability. Lipid-free apoB induced apoptosis in J774 macrophages assessed by caspase-3 activation and annexin V binding. LDL receptor, heparan sulfate proteoglycans, and class A scavenger receptor were involved in the binding/uptake of lipid-free apoB, but lipid-free apoB binding/uptake by the cells did not correlate with cytotoxicity. Lipid-free apoB disrupted the lipid bilayer of large unilamellar vesicles containing calcein. We evaluated the interaction between apoB and cellular membrane by monitoring the change in intracellular Ca2+ concentration using Fura-2, and found that lipid-free apoB rapidly disrupted the cellular membrane in the absence or presence of the inhibitors for cellular binding/uptake mediated by the receptors. Therefore, it is suggested that lipid-free apoB induces cell death by disturbance of the plasma membrane. In addition to other lipid component in modified LDL, apoB itself has an ability to induce apoptosis and plays a crucial role in the development of atherosclerotic lesions.
Keywords:apoB  apolipoprotein B  LDL  low density lipoprotein  NaDC  sodium deoxycholate  free apoB  lipid-free apoB  LDL-apoB  apoB bound to LDL  apoA-I  apolipoprotein A-I  BSA  bovine serum albumin  SRA  class A scavenger receptor  DMEM  Dulbecco's modified Eagle's medium  FBS  fetal bovine serum  LDH  lactate dehydrogenase  HSPG  heparan sulfate proteoglycan  LUV  large unilamellar vesicles  EGTA  ethyleneglycol-bis-(β-aminoethylether)-N  N  N&prime    N&prime  -tetraacetic acid
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