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 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 triglycerid