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

Background/Aim: Apolipoprotein (apo) E-deficiency leads to hepatic steatosi s and impaired Very Low Density Lipoprotein (VLDL)-triglyceride production rates in mice, A mutant apoE isoform, apoE3-Leiden, is associated with a do minantly inherited form of dysbetalipoproteinemia in humans. The aim of thi s 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 strai ns with different expression of the APOE*3-Leiden transgene with and withou t co-expression of human APOCI. Results: Hepatic triglyceride content was increased to maximally 233% of co ntrol values, depending on hepatic APOE*3-Leiden expression, Hepatic secret ion of VLDL-associated triglycerides was impaired (-20%) in high-expressing transgenics, with a concomitant increase from 1.6 to 8.1 of the apoB48/ ap oB100 ratio in newly-formed VLDL, Hepatocytes of the transgenic mice contai ned characteristic inclusions, up to 20 mu m in diameter, in numbers depend ent on APOE*3-Leiden expression and independent of APOCI expression, These inclusions contained material positively reacting with antihuman apoE antib odies, Immunogold-labeling confirmed the presence of apoE3-Leiden within th ese inclusions and also revealed the presence of the mutant protein on sinu soidal membranes, in multivesicular bodies and in peroxisomes, i.e., a dist ribution pattern similar to that of endogenous apoE in rodents. Nascent VLD L particles associated with the Golgi apparatus were also labeled. Conclusion: This study has demonstrated that introduction of human apoE3-Le iden in mice, in addition to its reported effects on lipolysis and lipoprot ein clearance, leads to hepatic deposition of the mutant apolipoprotein, de velopment of fatty liver and to altered hepatic VLDL secretion. The latter findings are consistent with a role of apoE in the regulation of intrahepat ic lipid metabolism.