Familial HDL Deficiency Characterized by Hypercatabolism of Mature ApoA-I but Not ProApoA-I

Abstract

Abstract-We have previously described patients with familial high density lipoprotein (HDL) deficiency (FHD) having a marked reduction in the plasma concentration of HDL cholesterol and apolipoprotein (apo) A-I but lacking clinical manifestations of Tangier disease or evidence of other known causes of HDL deficiency. To determine whether FHD in these individuals was associated with impaired HDL production or increased HDL catabolism, we investigated the kinetics of plasma apoA-I and apoA-II in two related FHD patients (plasma apoA-I, 17 and 37 mg/dL) and four control subjects (apoA-I, 126Ϯ18 mg/dL, meanϮSD) by using a primed constant infusion of deuterated leucine. Kinetic analysis of plasma apolipoprotein enrichment curves demonstrated that mature plasma apoA-I production rates (PRs) were similar in patients and control subjects (7.9 and 9.1 versus 10.5Ϯ1.7 mg ⅐ kg). Residence times (RTs) of mature apoA-I were, however, significantly less in FHD patients (0.79 and 1.66 days) compared with controls (5.32Ϯ1.05 days). Essentially normal levels of plasma proapoA-I (the precursor protein of apoA-I) in FHD patients were associated with normal plasma proapoA-I PRs (7.8 and 10.4 versus 10.9Ϯ2.6 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) and proapoA-I RTs (0.18 and 0.15 versus 0.16Ϯ0.03 day). The RTs of apoA-II were, however, less in patients (3.17 and 2.92 days) than control subjects (7.24Ϯ0.71 days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versus 1.7Ϯ0.2 mg ⅐ kg. Increased plasma catabolism of apoA-II in FHD patients was associated with the presence in plasma of abnormal apoA-II-HDL (without apoA-I). These results demonstrate that FHD in our patients is characterized, like Tangier disease, by hypercatabolism of mature apoA-I and apoA-II, but unlike Tangier disease, by essentially normal plasma catabolism and concentration of proapoA-I. (Arterioscler Thromb Vasc Biol. 1998;18:655-664.)

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

“…3 Thus, our approach is a reasonable method for determining apoA-I turn-over rate and is now widely used. 3,27,28 The kinetic parameters obtained for apoA-I in control subjects are in good agreement with results obtained in previous studies using stable isotopes 3 or radioiodinated apoA-I. 29,30 The true plateau value for apoA-I, corresponding to the proapoA-I plateau, has been shown to be about 80% of VLDL apo B100 plateau 28 for control subjects, indicating that apoA-I precursor enrichment is well approximated by VLDL apo B100 plateau.…”

Cellular Cholesterol Transport and Efflux in Fibroblasts Are Abnormal in Subjects With Familial HDL Deficiency

“…Pro-apoA-I, however was not catabolized faster in FHD subjects compared with controls. 43 This datum suggests that after entering the plasma pool, apoA-I-containing lipoproteins are unable to obtain cellular phospholipids and cholesterol and that these particles are predominantly pre-␤-migrating and rapidly cleared from plasma.…”

Apolipoprotein A-I Activates Cellular cAMP Signaling through the ABCA1 Transporter

“…The importance of ABCA1 in the reverse cholesterol transport process has been strikingly demonstrated by the identification of mutations in ABCA1 gene locus as the molecular defect of Tangier disease (TD) and familial HDL deficiency (4,5). These patients are characterized by extremely low HDL levels caused by inadequate transport of cellular cholesterol and phospholipids to the extracellular space, leading to hypercatabolism of lipid-poor nascent HDL particles (6). Thus, factors affecting the active lipidation of apoA-I are likely to affect the homeostasis of plasma HDL cholesterol and the reverse cholesterol transport process, one of the major mechanisms by which HDL may prevent atherosclerotic vascular disease (7).…”