High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells

Abstract

Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI-mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCA1 and SR-B1 but not involving PI3K and Akt.

Transport of Apolipoprotein B-Containing Lipoproteins through Endothelial Cells Is Associated with Apolipoprotein E-Carrying HDL-Like Particle Formation

“…In brief, 300 µCi of 3 H-Ch was incubated with 50 mL human serum containing 50 µM butylated hydroxytoluene at 37 °C for 18 h. The unassociated 3 H-Ch was removed by incubation with an equal volume of autologous packed erythrocytes at 37 °C for 2 h. The erythrocytes were removed by centrifugation at 16,000× g at 4 °C for 5 min. Radiolabeled E/B-LPs ( d ≤ 1.019), TRLs ( d ≤ 1.006), IDLs ( d = 1.006–1.019), and LDLs ( d = 1.019–1.063) were isolated by potassium bromide (KBr) DG ultracentrifugation, as previously described [ 35 ]. The E/B-LPs, TRLs, IDLs, and LDLs labeled in this manner contained both esterified and free 3 H-Ch [ 34 ].…”

Mangiferin promotes macrophage cholesterol efflux and protects against atherosclerosis by augmenting the expression of ABCA1 and ABCG1

“…The initial and key step of RCT is ATP-binding cassette transporter A1/G1 (ABCA1/G1)-mediated cholesterol efflux from nonhepatic peripheral tissues (e.g. macrophages and vascular smooth muscle cells) to extracellular lipid acceptors, resulting in HDL formation [5]. Tangier disease is characterized by the absence of HDL cholesterol (HDL-C) from plasma and increased susceptibility to CVD [6].…”

Atherogenesis, Transcytosis, and the Transmural Cholesterol Flux: A Critical Review

“…In diseased atherosclerotic arteries, where adventitial lymphatic vessels expand and grow in number, the cholesterol-loaded HDL particles can then find their way back to the circulation through arterial lymphatics [ 24 , 25 ]. Yet, intimal HDL particles in normal arteries probably return to the circulation by diffusion and transcytosis in the reverse basolateral-to-apical direction [ 7 , 26 ]. Vaisman et al [ 7 ] speculated that cholesterol from intimal HDL particles can be taken up by basolateral SR-B1 receptors and then transported across the endothelial cells as free cholesterol, to be picked up again by apical SR-B1 receptors and plasma HDL.…”