Abstract
The severe depletion of cholesteryl ester (CE) in adrenocortical cells of apoA-I(-/-) mice suggests that apolipoprotein (apo) A-I plays an important role in the high density lipoprotein (HDL) CE selective uptake process mediated by scavenger receptor BI (SR-BI) in vivo. A recent study showed that apoA-I(-/-) HDL binds to SR-BI with the same affinity as apoA-I(+/+) HDL, but apoA-I(-/-) HDL has a decreased V(max) for CE transfer from the HDL particle to adrenal cells. The present study was designed to determine the basis for the reduced selective uptake of CE from apoA-I(-/-) HDL. Variations in apoA-I(-/-) HDL particle diameter, free cholesterol or phospholipid content, or the apoE or apoA-II content of apoA-I(-/-) HDL had little effect on HDL CE selective uptake into Y1-BS1 adrenal cells. Lecithin cholesterol acyltransferase treatment alone or addition of apoA-I to apoA-I(-/-) HDL alone also had little effect. However, addition of apoA-I to apoA-I(-/-) HDL in the presence of lecithin cholesterol acyltransferase reorganized the large heterogeneous apoA-I(-/-) HDL to a more discrete particle with enhanced CE selective uptake activity. These results show a unique role for apoA-I in HDL CE selective uptake that is distinct from its role as a ligand for HDL binding to SR-BI. These data suggest that the conformation of apoA-I at the HDL surface is important for the efficient transfer of CE to the cell.
Highlights
Role of Apolipoprotein Content and Particle Size in Reduced cholesteryl ester (CE) Selective Uptake Activity of ApoA-IϪ/Ϫ HDL—Previous studies with reconstituted or modified HDL suggest that specific apolipoproteins, apoA-II and apoE, may alter the efficiency of SR-BI-mediated HDL CE selective uptake
Comparing particles isolated from mice of the same genetic strain, ϳ2-fold more selective CE uptake was observed from apoA-Iϩ/ϩ than from apoA-IϪ/Ϫ HDL (Fig. 1D)
The results from this study indicate that the reduced efficiency of CE selective uptake from apoA-IϪ/Ϫ HDL into adrenal cells is caused by the physical absence of apoA-I
Summary
Mice deficient in apoA-I have a 70% reduction in total plasma cholesterol and HDL cholesterol [5,6,7], a 75% reduction in LCAT activity [8], and a severe depletion of cholesteryl ester stores in steroidogenic tissues [9] In these animals, the cortical cells of the adrenal gland, the luteal and interstitial cells of the ovary, and the Leydig cells of the testis all display diminished CE content, indicating that apoA-I is important for the SR-BI-mediated HDL CE selective uptake process [10, 11]. Addition of apoA-I to apoA-IϪ/Ϫ HDL in the presence of LCAT reorganized HDL structure and produced an HDL particle with enhanced CE selective uptake activity These data suggest that the conformation of apoA-I at the HDL surface is important for the efficient transfer of CE to the cell
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