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 r ate. To establish the role of apoE in the regulation of hepatic VLDL produc tion, the human APOE3 gene was introduced into apoE-deficient mice by cross -breeding with APOE3 transgenics (APOE3/apoe-/- mice) or by adenoviral tran sduction, APOE3 was expressed in the liver and, to a lesser extent, in brai n, 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 elevate d when compared with wild type control values (1.9 +/- 0.1 mar). Hepatic tr iglyceride accumulation in apoE-deficient mice was completely reversed by i ntroduction of the APOE3 transgene, The in vivo hepatic VLDL-triglyceride p roduction rate was reduced to 36% of control values in apoE-deficient mice but normalized in APOE3/ apoe-/- mice. Hepatic secretion of apoB was not af fected in either of the strains. Secretion of H-3-labeled triglycerides syn thesized from [H-3]glycerol by cultured hepatocytes from apoE-deficient mic e was four times lower than by APOE3/apoe-/- or control hepatocytes. The av erage size of secreted VLDL particles produced by cultured apoE-deficient h epatocytes was significantly reduced when compared with those of APOE3/ apo e-/- and wild type mice. Hepatic expression of human APOE3 cDNA via adenovi rus-mediated gene transfer in apoE-deficient mice resulted in a reduction o f plasma cholesterol depending on plasma apoE3 levels. The in vivo VLDL-tri glyceride production rate in these mice was increased up to 500% compared w ith LacZ-injected controls and correlated with the amount of apoE3 per part icle. These findings indicate a regulatory role of apoE in hepatic VLDL-tri glyceride secretion, independent from its role in lipoprotein clearance.