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J Biol Chem, Vol. 274, Issue 50, 35711-35718, December 10, 1999
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From the Groningen Institute for Drug Studies, Departments of
ApoE-deficient mice on low fat diet
show hepatic triglyceride accumulation and a reduced very low density
lipoprotein (VLDL) triglyceride production rate. To establish the role
of apoE in the regulation of hepatic VLDL production, the human APOE3
gene was introduced into apoE-deficient mice by cross-breeding with APOE3 transgenics (APOE3/apoe Pediatrics and ¶ Pathology, University Hospital
Groningen, 9713 GZ Groningen, the § Gaubius Laboratory, TNO
Prevention and Health, 2301 CE Leiden, Leiden University Medical
Center, the Departments of ** Human Genetics,
§§ Cardiology, and ¶¶ Internal Medicine, 2300 RA
Leiden, and the Laboratory of Cell Biology and Biomaterials,
Faculty of Medical Sciences, University of Groningen,
9712 KZ Groningen, the Netherlands
/ mice) or by adenoviral
transduction. APOE3 was expressed in the liver and, to a lesser extent,
in brain, spleen, and lung of transgenic APOE3/apoe/
mice similar to endogenous apoe. Plasma cholesterol levels
in APOE/apoe/ mice (3.4 ± 0.5 mM)
were reduced when compared with apoe/ mice (12.6 ± 1.4 mM) but still elevated when compared with wild type
control values (1.9 ± 0.1 mM). Hepatic triglyceride
accumulation in apoE-deficient mice was completely reversed by
introduction of the APOE3 transgene. The in vivo hepatic
VLDL-triglyceride production rate was reduced to 36% of control values
in apoE-deficient mice but normalized in APOE3/apoe/
mice. Hepatic secretion of apoB was not affected in either of the
strains. Secretion of 3H-labeled triglycerides synthesized
from [3H]glycerol by cultured hepatocytes from
apoE-deficient mice was four times lower than by
APOE3/apoe/ or control hepatocytes. The average size of
secreted VLDL particles produced by cultured apoE-deficient hepatocytes
was significantly reduced when compared with those of
APOE3/apoe/ and wild type mice. Hepatic expression of
human APOE3 cDNA via adenovirus-mediated gene transfer in
apoE-deficient mice resulted in a reduction of plasma cholesterol
depending on plasma apoE3 levels. The in vivo
VLDL-triglyceride production rate in these mice was increased up to
500% compared with LacZ-injected controls and correlated with the
amount of apoE3 per particle. These findings indicate a regulatory role
of apoE in hepatic VLDL-triglyceride secretion, independent from its
role in lipoprotein clearance.
Established investigator of the Netherlands Heart Foundation.
To whom correspondence should be addressed:
Center for Liver, Digestive and Metabolic Diseases, Groningen Inst. for
Drug Studies, Rm. Y2115, CMC IV, University Hospital Groningen,
Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Tel.: 31-50-363-2669;
Fax: 31-50-361-1746; E-mail: f.kuipers@med.rug.nl.
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