Reverse Cholesterol Transport in Plasma of Patients With Different Forms of Familial HDL Deficiency

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Abstract
Abstract HDLs encompass structurally heterogenous lipoproteins that fulfill specific functions in reverse cholesterol transport. Two-dimensional nondenaturing gradient gel electrophoresis (2D-PAGGE) of normoalphalipoproteinemic plasma and subsequent immunoblotting with anti–apoA-I-antibodies differentiates pre-β 1 -LpA-I, pre-β 2 -LpA-I, pre-β 3 -LpA-I, α-LpA-I 2 , and α-LpA-I 3 . Immunodetection with anti-apoE antibodies differentiates γ-LpE and α-LpE. Pulse-chase incubations of plasma with [ 3 H]unesterified cholesterol ([ 3 H]UC)–labeled fibroblasts and subsequent 2D-PAGGE revealed that cell-derived [ 3 H]UC is taken up by pre-β 1 -LpA-I and γ-LpE. From these initial acceptors, [ 3 H]UC is transferred to LDL via pre-β 2 -LpA-I→pre-β 3 -LpA-I→α-LpA-I. Some UC is esterified in pre-β 3 -LpA-I, and some is esterified in α-LpA-I after its retransfer from LDL. In this study we investigated the effect of various forms of familial HDL deficiency on reverse cholesterol transport. Plasma samples of patients with various forms of HDL deficiency are characterized by the lack of specific HDL subclasses. ApoE-containing HDLs, including γ-LpE, are present in all kinds of HDL deficiency. However, all forms of LpA-I are absent in apoA-I–deficient plasma, pre-β 3 -LpA-I and α-LpA-I from the plasma of patients with Tangier disease (TD), and pre-β 3 -LpA-I and large α-LpA-I from the plasma of patients with lecithin:cholesterol acyltransferase (LCAT) deficiency and fish-eye disease (FED). After a 1-minute pulse with labeled fibroblasts, efflux of [ 3 H]UC into HDL-deficient plasmas decreased, compared with normal plasma, by 49% (apoA-I deficiency), 36% (TD), 21% (LCAT deficiency), and 28% (FED). In apoA-I deficiency, only γ-LpE takes up cell-derived [ 3 H]UC. In the three other HDL-deficiency states, cell-derived [ 3 H]UC is initially taken up by both pre-β 1 -LpA-I and γ-LpE. The four HDL deficiencies are also characterized by differences in the esterification of cell-derived [ 3 H]UC. No esterification occurs in LCAT-deficient plasma. In FED plasma, [ 3 H]UC is esterified in LDL. In apoA-I deficiency and TD, however, [ 3 H]UC is esterified in lipoproteins free of apoA-I and apoB. In the two latter cases, the transfer of [ 3 H]cholesteryl ester to LDL is enhanced compared with normal plasma. The lack of specific HDL subclasses and the consequent changes in reverse cholesterol transport pathways differently affect net mass efflux of cholesterol from fibroblasts into HDL-deficient plasma. Compared with normoalphalipoproteinemic plasma, net cholesterol efflux from fibroblasts into plasma is reduced by 48%, 12%, 60%, and 34% in apoA-I deficiency, TD, LCAT deficiency, and FED, respectively. Removal of apoB-containing lipoproteins from plasma of patients with apoA-I deficiency, TD, LCAT deficiency, and FED further decreased net cholesterol efflux rates by 77%, 84%, 72%, and 64%, respectively, compared with a reduction of 39% in normoalphalipoproteinemic control plasma. In conclusion, various quantitatively minor HDL subfractions and LDL also present in HDL-deficient plasma effectively contribute to reverse cholesterol transport.

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