Apolipoprotein E participates in the regulation of very low density lipoprotein-triglyceride secretion by the liver.
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 (3)H-labeled triglycerides synthesized from [(3)H]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.
Mensenkamp
A R
AR
Groningen Institute for Drug Studies, University Hospital Groningen, 9713 GZ Groningen.
Jong
M C
MC
van Goor
H
H
van Luyn
M J
MJ
Bloks
V
V
Havinga
R
R
Voshol
P J
PJ
Hofker
M H
MH
van Dijk
K W
KW
Havekes
L M
LM
Kuipers
F
F
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000097:blood; D003433:Crosses, Genetic; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005990:Glycerol / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D010840:Phytosterols; D012855:Sitosterols / Q000097:blood; D013261:Sterols / Q000097:blood*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*; D014316:Tritium
D001057:Apolipoproteins E; D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D010840:Phytosterols; D012855:Sitosterols; D013261:Sterols; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D014316:Tritium; C021273:campesterol; C025473:gamma-sitosterol; C001521:lathosterol; D002784:Cholesterol; D005990:Glycerol