INCREASED PLASMA AND RENAL CLEARANCE OF AN EXCHANGEABLE POOL OF APOLIPOPROTEIN A-I IN SUBJECTS WITH LOW-LEVELS OF HIGH-DENSITY-LIPOPROTEIN CHOLESTEROL

Plasma levels of HDL apo A-I are reduced in individuals with low HDL c holesterol (HDL-C) concentrations as a result of increased fractional catabolic rates (FCRs). To determine the basis for the high apo A-I FC Rs, seven subjects with low HDL-C levels (31.0+/-4.3 mg/dl) were compa red with three subjects with high HDL-C levels (72.0+/-4.5 mg/dl). Eac h subject received autologous HDL that was labeled directly by the iod ine-monochloride method (whole-labeled) and autologous HDL that was la beled by exchange with homologous radiolabeled apo A-I (exchange-label ed). Blood was obtained for 2 wk, specific activities determined, and FCRs (d-1+/-SD) estimated. In every subject, whether in the low or hig h HDL-C group, the exchange-labeled FCR was greater than the whole-lab eled FCR. The exchange-labeled FCR was higher in the low HDL-C group ( 0.339+/-0.043) versus the high HDL-C group (0.234+/-0.047; P < 0.009). The whole-labeled FCR was also greater in the low HDL-C group (0.239/-0.023) versus the high HDL-C group (0.161+/-0.064; P < 0.02). In add ition, in both low and high HDL groups ultracentrifugation resulted in more radioactivity in d > 1.210 (as percentage of total plasma counts per minute) with the exchange-labeled tracer than with the whole-labe led tracer (12.55+/-4.95% vs. 1.02+/-0.38%; P < 0.003). With both HDL tracers, more radioactivity was found in d > 1.210 in the low versus t he high HDL-C groups. When apo A-I catabolism was studied by perfusing isolated rabbit kidneys with whole-labeled HDL, there was twice as mu ch accumulation (cpm/g cortex) of HDL apo A-I isolated from subjects w ith low HDL-C than from subjects with high HDL-C (P < 0.0025). Finally , HDL that had been isolated from subjects with high levels of HDL-C w as triglyceride enriched and exposed to partially purified lipases bef ore perfusion through kidneys. Threefold more apo A-I from modified HD L accumulated in the cortex compared with the unmodified preparation ( P < 0.007). The results of these in vivo and ex vivo studies indicate that individuals with low HDL-C levels have more loosely bound, easily exchanged apo A-I and that this exchangeable apo A-I is more readily cleared by the kidney.