Title
Apolipoprotein E participates in the regulation of very low density lipoprotein-triglyceride secretion by the liver
Author
TNO Preventie en Gezondheid
Mensenkamp, A.R.
Jong, M.C.
van Goor, H.
van Luyn, M.J.A.
Bloks, V.
Havinga, R.
Voshol, P.J.
Hofker, M.H.
van Dijk, K.W.
Havekes, L.M.
Kuipers, F.
Publication year
1999
Abstract
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-/- 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 all-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. Chemicals/CAS: Apolipoproteins E; campesterol, 474-62-4; Cholesterol, 57-88-5; Fatty Acids, Nonesterified; Glycerol, 56-81-5; lathosterol, 80-99-9; Lipoproteins; Lipoproteins, VLDL; Phytosterols; sitosterol, 5779-62-4; Sitosterols; Sterols; Triglycerides; Tritium, 10028-17-8; very low density lipoprotein triglyceride
Subject
Animals
Apolipoproteins E
Cells, Cultured
Cholesterol
Crosses, Genetic
Fatty Acids, Nonesterified
Glycerol
Homeostasis
Humans
Lipoproteins
Lipoproteins, VLDL
Liver
Mice
Mice, Knockout
Mice, Transgenic
Microscopy, Immunoelectron
Phytosterols
Sitosterols
Sterols
Triglycerides
Tritium
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DOI
https://doi.org/10.1074/jbc.274.50.35711
TNO identifier
235348
ISSN
0021-9258
Source
Journal of Biological Chemistry, 274 (274), 35711-35718
Document type
article