Probing the pathways of chylomicron and HDL metabolism using adenovirus-mediated gene transfer

Abstract

New insights are provided into the role of apoE in cholesterol and triglyceride homeostasis, and of apoA-I in the biogenesis of HDL. Clearance of the lipoprotein remnants and increase in HDL synthesis are obvious targets for therapeutic interventions.

Generation of a Recombinant Apolipoprotein E Variant with Improved Biological Functions

“…It was found that, consistent with previous findings (12)(13)(14)(15)(16), the rate of triglyceride secretion increased 6.5-fold in mice infected with adenoviruses expressing WT apoE4 as compared with mice infected with AdGFP control. In mice infected with adenoviruses expressing either apoE-mut1 or apoE4-mut2, the rate of VLDL triglyceride secretion increased 1.9-fold as compared with mice infected with the control adenoviruses but was only 27% of the rate of VLDL secretion observed in mice infected with the apoE4-expressing adenovirus (Fig.…”

“…Finally, truncated apoE forms could not correct the high cholesterol profiles of the apoE Ϫ/Ϫ ϫ LDLr Ϫ/Ϫ double-deficient mice but did not induce hypertriglyceridemia, indicating that the carboxyl-terminal region of apoE is responsible for the hypertriglyceridemia (15, 16). Use of a series of apoE deletion mutants extending from amino acid 1 to amino acids 185, 202, 229, or 259 mapped the region responsible for the hypertriglyceridemia between amino acids 260 and 299 of apoE (12)(13)(14)(15)(16)(17). This region contains two hydrophobic stretches of amino acids between residues 261-269 and 276 -283.…”

“…It was shown that overexpression of full-length apoE (by infection of mice with 1-2 ϫ 10 9 pfu) did not correct the high cholesterol levels of the apoE Ϫ/Ϫ mice, in contrast, it increased VLDL triglyceride secretion and induced hypertriglyceridemia (12)(13)(14)(15)(16). Overexpression of apoE3 or apoE4 also aggravated the hypercholesterolemia in apoE2 knock-in mice (17).…”

“…Overexpression of apoE3 or apoE4 also aggravated the hypercholesterolemia in apoE2 knock-in mice (17). However the high cholesterol profile of apoE Ϫ/Ϫ mice or the apoE2 knock-in mice was corrected by infection with truncated apoE forms lacking different segments of the carboxyl-terminal domain (12)(13)(14)(15)(16)(17). The hypertriglyceridemia induced by full-length apoE was independent of the apoE phenotype and mouse strain and could be corrected by overexpression of lipoprotein lipase (15).…”

Surface Tensiometry of Apolipoprotein B Domains at Lipid Interfaces Suggests a New Model for the Initial Steps in Triglyceride-rich Lipoprotein Assembly

“…The remaining particle remnants are smaller, more dense, and enriched in cholesterol esters. Low density lipoprotein (LDL) is the remnant particle of VLDL (1,2), and high plasma concentrations of LDL are associated with heart attack and stroke (3).…”