Hepatic lipid accumulation, altered very low density lipoprotein formation and apolipoprotein E deposition in apolipoprotein E3-Leiden transgenic mice

Abstract

Background/Aim: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 dys-betalipoproteinemia 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 μm 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.Conclusion: 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.