Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT

Abstract

We have investigated the ability of apoE (apolipoprotein E) to participate in the biogenesis of HDL (high-density lipoprotein) particles in vivo using adenovirus-mediated gene transfer in apoA-I-/- (apolipoprotein A-I) or ABCA1-/- (ATP-binding cassette A1) mice. Infection of apoA-I-/- mice with 2x10(9) pfu (plaque-forming units) of an apoE4-expressing adenovirus increased both HDL and the triacylglycerol-rich VLDL (very-low-density lipoprotein)/IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein) fraction and generated discoidal HDL particles. ABCA1-/- mice treated similarly failed to form HDL particles, suggesting that ABCA1 is essential for the generation of apoE-containing HDL. Combined infection of apoA-I-/- mice with a mixture of adenoviruses expressing both apoE4 (2x10(9) pfu) and human LCAT (lecithin:cholesterol acyltransferase) (5x10(8) pfu) cleared the triacylglycerol-rich lipoproteins, increased HDL and converted the discoidal HDL into spherical HDL. Similarly, co-infection of apoE-/- mice with apoE4 and human LCAT corrected the hypercholesterolaemia and generated spherical particles, suggesting that LCAT is essential for the maturation of apoE-containing HDL. Overall, the findings indicate that apoE has a dual functionality. In addition to its documented functions in the clearance of triacylglycerol-rich lipoproteins, it participates in the biogenesis of HDL-sized apoE-containing particles. HDL particles generated by this pathway may account at least for some of the atheroprotective functions of apoE.

Molecular bases of copper and iron deficiency-associated dyslipidemia: a microarray analysis of the rat intestinal transcriptome

“…Lipid composition of HDL copper-deficient rats does not differ from that of copper adequate animals, unlike the ApoE fraction that shows a considerable enrichment [13,14]. Physiological concentrations of ApoE ensure the lipid homeostasis and its anti-atherogenic effects, while higher concentrations of ApoE are responsible for the spherical to discoidal transformation of HDL, which makes them unable to bind to the liver LDL receptors and slow down the retrograde transport of CL [15]. On the other hand, lecithin:cholesterol acyltransferase (LCAT) catalyzes the esterification of free CL in the HDL, contributing to the lipoprotein maturation and to the shape transition from the discoidal to the spherical form, but plasma LCAT activity in copper-deficient rats is considerably reduced [16].…”

ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT

“…These functional interactions catalyze the transfer of phospholipids and subsequently cholesterol from intracellular membrane pools to lipidfree apoA-I or apoE leading to the formation of minimally lipidated particles which are gradually converted to discoidal particles ( 39,47,55,56 ). Subsequent esterifi cation of the cholesterol of the nascent pre-␤ and discoidal particles by LCAT generates the spherical HDL particles present in the plasma that can be visualized by EM ( 55,56 ). In the present study the ability of apoA-IV to promote de novo formation of HDL-A-IV particles was established by adenovirus mediated gene transfer in four different mouse models.…”

Recent advances in physiological lipoprotein metabolism

“…On the basis of studies using synthetic peptide mimics of apolipoproteins it appears that the key structural motif necessary for an apolipoprotein to function as a lipid acceptor is the presence amphipathic helices [201]. Studies in mice suggest that in addition to its role in clearing TG rich lipoproteins apoE participates in the biogenesis of apoE containing HDL particles with the participation of ABCA1 [202]. It is likely, however, that the concentration of lipid poor apolipoprotein in the extracellular fluid is more relevant for ABCA1 efflux (Figure 4).…”