FAMILIAL HDL DEFICIENCY CHARACTERIZED BY HYPERCATABOLISM OF MATURE APOA-I BUT NOT PROAPOA-I

We have previously described patients with familial high density lipop rotein (HDL) deficiency (FHD) having a marked reduction in the plasma concentration of HDL cholesterol and apolipoprotein (apo) A-I but lack ing clinical manifestations of Tangier disease or evidence of other kn own causes of HDL deficiency. To determine whether FHD in these indivi duals was associated with impaired HDL production or increased HDL cat abolism? 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 con trol subjects (apoA-I, 126+/-18 mg/dL, mean+/SD) by using a primed con stant infusion of deuterated leucine. Kinetic analysis of plasma apoli poprotein enrichment curves demonstrated that mature plasma apoA-I pro duction rates (PRs) were similar in patients and control subjects (7.9 and 9.1 versus 10.5+/-1.7 mg . kg(-1) . d(-1)). Residence times (RTs) of mature apoA-I were, however, significantly less in FHD patients (0 .79 and 1.66 days) compared with controls (5.32+/-1.05 days). Essentia lly 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 10.9+/-2.6 mg . kg(-1) . d(-1)) and proapoA-I RTs (0 .18 and 0.15 versus 0.16+/-0.03 day). The RTs of apoA-II were, however , less in patients (3.17 and 2.92 days) than control subjects (7.24+/- 0.71 days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versu s 1.7+/-0.2 mg . kg(-1) d(-1)). Increased plasma catabolism of apoA-II in FHD patients was associated with the presence in plasma of abnorma l apoA-II-HDL (without apoA-I), These results demonstrate that FHD in our patients is characterized, like Tangier disease, by hypercatabolis m of mature apoA-I and apoA-II, but unlike Tangier disease, by essenti ally normal plasma catabolism and concentration of proapoA-I.