Plasma clearance of human low-density lipoprotein in human apolipoprotein B transgenic mice is related to particle diameter.
To test for intrinsic differences in metabolic properties of low-density lipoprotein (LDL) as a function of particle size, we examined the kinetic behavior of 6 human LDL fractions ranging in size from 251 to 265 A injected intravenously into human apolipoprotein (apo) B transgenic mice. A multicompartmental model was formulated and fitted to the data by standard nonlinear regression using the Simulation, Analysis and Modeling (SAAM II) program. Smaller sized LDL particles (251 to 257 A) demonstrated a significantly slower fractional catabolic rate (FCR) (0.050 +/- 0.045 h(-1)) compared with particles of larger size (262 to 265 A) (0.134 +/- -0.015 h(-1), P <.03), and there was a significant correlation between FCR and the peak LDL diameter of the injected fractions (R(2) =.71, P <.034). The sum of the equilibration parameters, k(2,1) and k(1,2), for smaller LDL (0.255 h(-1) and 0.105 h(-1), respectively) was significantly smaller than that for larger LDL (0.277 h(-1) and 0.248 h(-1), respectively; P <.01), indicative of slower intravascular-extravascular exchange for smaller LDL. Therefore in this mouse model, smaller LDL particles are cleared more slowly from plasma than larger LDL and are exchanged more slowly with the extravascular space. This might be due to compositional or structural features of smaller LDL that lead to retarded clearance.
Berneis
Kaspar
K
Donner Laboratory, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA.
Shames
David M
DM
Blanche
Patricia J
PJ
La Belle
Michael
M
Rizzo
Manfredi
M
Krauss
Ronald M
RM
D000328:Adult; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics*; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D023421:Models, Animal; D010316:Particle Size; D017035:Pravastatin / Q000627:therapeutic use; D012044:Regression Analysis; D019821:Simvastatin / Q000627:therapeutic use
D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D019821:Simvastatin; D017035:Pravastatin