INVIVO METABOLISM OF A MUTANT FORM OF APOLIPOPROTEIN A-I, APO A-I(MILANO), ASSOCIATED WITH FAMILIAL HYPOALPHALIPOPROTEINEMIA

Apo A-I(Milano) is a mutant form of apo A-I in which cysteine is subst ituted for arginine at amino acid 173. Subjects with apo A-I(Milano) a re characterized by having low levels of plasma HDL cholesterol and ap o A-I. To determine the kinetic etiology of the decreased plasma level s of the apo A-I in these individuals, normal and mutant apo A-I were isolated, radiolabeled with either I-125 or I-131, and both types of a po A-I were simultaneously injected into two normal control subjects a nd two subjects heterozygous for apo A-I(Milano). In the normal subjec ts, apo A-I(Milano) was catabolized more rapidly than the normal apo A -I (mean residence times of 5.11 d for normal apo A-I vs. 3.91 d for a po A-I(Milano)), clearly establishing that apo A-I(Milano) is kinetica lly abnormal and that it has a shortened residence time in plasma. In the two apo A-I(Milano) subjects, both types of apo A-I were cataboliz ed more rapidly than normal (residence times ranging from 2.63 to 3.70 d) with normal total apo A-I production rates (mean of 10.3 vs. 10.4 mg/kg per d in the normal subjects). Therefore, in the subjects with a po A-I(Milano), the decreased apo A-I levels are caused by rapid catab olism of apo A-I and not to a decreased production rate, and the abnor mal apo A-I(Milano) leads to the rapid catabolism of both the normal a nd mutant forms of apo A-I in the affected subjects.