Hepatic lipid accumulation, altered very low density lipoprotein formation and apolipoprotein E deposition in apolipoprotein E3-Leiden transgenic mice.
OBJECTIVE
Apolipoprotein (apo) E-deficiency leads to hepatic steatosis and impaired Very Low Density Lipoprotein (VLDL)-triglyceride production rates in mice. A mutant apoE isoform, apoE3-Leiden, is associated with a dominantly inherited form of dysbetalipoproteinemia in humans. The aim of this study was to evaluate the effects of APOE*3-Leiden expression on hepatic lipid content, VLDL formation and liver morphology in mice.


METHODS
Comparison of lipid parameters and liver morphology in mouse strains with different expression of the APOE*3-Leiden transgene with and without co-expression of human APOCI.


RESULTS
Hepatic triglyceride content was increased to maximally 233% of control values, depending on hepatic APOE*3-Leiden expression. Hepatic secretion of VLDL-associated triglycerides was impaired (-20%) in high-expressing transgenics, with a concomitant increase from 1.6 to 8.1 of the apoB48/ apoB100 ratio in newly-formed VLDL. Hepatocytes of the transgenic mice contained characteristic inclusions, up to 20 microm in diameter, in numbers dependent on APOE*3-Leiden expression and independent of APOCI expression. These inclusions contained material positively reacting with antihuman apoE antibodies. Immunogold-labeling confirmed the presence of apoE3-Leiden within these inclusions and also revealed the presence of the mutant protein on sinusoidal membranes, in multivesicular bodies and in peroxisomes, i.e., a distribution pattern similar to that of endogenous apoE in rodents. Nascent VLDL particles associated with the Golgi apparatus were also labeled.


CONCLUSIONS
This study has demonstrated that introduction of human apoE3-Leiden in mice, in addition to its reported effects on lipolysis and lipoprotein clearance, leads to hepatic deposition of the mutant apolipoprotein, development of fatty liver and to altered hepatic VLDL secretion. The latter findings are consistent with a role of apoE in the regulation of intrahepatic lipid metabolism.
Mensenkamp
A R
AR
Groningen University Institute for Drug Exploration, Center for Liver, Digestive and Metabolic Diseases, Faculty of Medical Sciences and University Hospital Groningen, The Netherlands.
van Luyn
M J
MJ
van Goor
H
H
Bloks
V
V
Apostel
F
F
Greeve
J
J
Hofker
M H
MH
Jong
M C
MC
van Vlijmen
B J
BJ
Havekes
L M
LM
Kuipers
F
F
D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D008055:Lipids; D008079:Lipoproteins, VLDL; C052720:apolipoprotein E3 (Leidein)