Tangier disease is a rare familial disorder characterized by extremely low levels of
apolipoprotein A-I (
apoA-I) and
high density lipoproteins (HDL). In normal subjects, proapoA-I is secreted into plasma and converted to mature
apoA-I by the cleavage of the amino-terminal six
amino acids with the major isoprotein in plasma being mature
apoA-I. In contrast, in
Tangier disease there is a marked relative increase of proapoA-I as compared with mature
apoA-I. ProapoA-I and mature
apoA-I were isolated from normal and
Tangier disease subjects, radio-labeled, and autologous
apoA-I isoproteins injected into normal and Tangier subjects. The in vivo catabolism and conversion of proapoA-I and mature
apoA-I in normal and
Tangier disease subjects were quantitated. A comparison of the rate of catabolism of
apoA-I isoproteins from plasma revealed a significantly faster rate of catabolism of both isoproteins of
apoA-I in Tangier subjects when compared with normal subjects. The fractional conversion rate of proapoA-I to mature
apoA-I was 3.9 d-1 in normal subjects and 3.6 d-1 in Tangier subjects. The results indicate that (a)
apoA-I enters plasma as the pro isoprotein in both normal and Tangier subjects, (b)
Tangier disease subjects have a normal fractional rate of conversion of proapoA-I to mature
apoA-I, (c) proapoA-I is catabolized at the same rate as mature
apoA-I in Tangier subjects, and (d) Tangier subjects catabolize both pro and mature
apoA-I at a much greater rate than do normal subjects. Therefore, the relative increase in proapoA-I in
Tangier disease is due to a marked decrease in mature
apoA-I resulting from rapid catabolism of both pro- and mature
apoA-I and not to defective conversion of proapoA-I to mature
apoA-I.