Role of the kidney in regulating the metabolism of HDL in rabbits: Evidence that iodination alters the catabolism of apolipoprotein A-I by the kidney

To evaluate the factors that regulate HDL catabolism in vivo, we have measu red the clearance of human apoA-I from rabbit plasma by following the isoto pic decay of I-125-apoA-I and the clearance of unlabeled apoA-I using a rad ioimmunometric assay (RIA). We show that the clearance of unlabeled apoA-I is 3-fold slower than that of I-125-apoA-I. The mass clearance of iodinated apoA-I, as determined by RTA, is superimposable with the isotopic clearanc e of I-125-apoA-I. The data demonstrate that iodination of tyrosine residue s alters the apoA-I molecule in a manner that promotes an accelerated catab olism. The clearance from rabbit plasma of unmodified apoA-I on HDL3 and a reconstituted HDL particle (LpA-I) were very similar and about 3-4-fold slo wer than that for I-125-apoA-I on the lipoproteins. Therefore, HDL turnover in the rabbit is much slower than that estimated from tracer kinetic studi es. To determine the role of the kidney in HDL metabolism, the kinetics of unmodified apoA-I and LpA-I were reevaluated in animals after a unilateral nephrectomy. Removal of one kidney was associated with a 40-50% reduction i n creatinine clearance rates and a 34% decrease in the clearance rate of un labeled apoA-I and LpA-I particles. In contrast, the clearance of I-125-lab eled molecules was much less affected by the removal of a kidney; FCR for I -125-LpA-I was reduced by <10%. The data show that the kidneys are responsi ble for most (70%) of the catabolism of apoA-I and HDL in vivo, while I-125 -labeled apoA-I and HDL are rapidly catabolized by different tissues. Thus, the kidney is the major site for HDL catabolism in vivo. Modification of t yrosine residues on apoA-I may increase its plasma clearance rate by enhanc ing extra-renal degradation pathways.