title: Rapid in vivo transport and catabolism of human apolipoprotein A-IV-1 and slower catabolism of the apoA-IV-2 isoprotein.
abstract: Apolipoprotein (apo) A-IV is a polymorphic, intestinally derived apolipoprotein that is genetically linked to and similar in structure to apoA-I, the major apolipoprotein in high density lipoproteins (HDL). ApoA-IV plays a potentially important role in lipoprotein metabolism and reverse cholesterol transport, but its in vivo metabolism is poorly understood. In order to gain insight into factors modulating apoA-IV metabolism in humans, the in vivo kinetics of the two major human apoA-IV isoproteins apoA-IV-1 and apoA-IV-2 were investigated in normolipidemic human subjects. 131I-apoA-IV-1 and 125I-apoA-IV-2 were reassociated with autologous plasma and injected into study subjects. Analysis of the kinetic data revealed a rapid mean fractional catabolic rate (FCR) for apoA-IV-1 of 2.42 +/- 0.11 d-1. The mean production, or transport, rate of apoA-IV-1 was 16.3 +/- 1.4 mg/kg per d. Plasma apoA-IV concentrations were highly correlated with apoA-IV production rate (r = 0.84, P < 0.001) and not correlated with apoA-IV fractional catabolic rate (r = 0.25, P = NS). The mean FCR of apoA-IV-2 was 2.21 +/- 0.10 d-1. In the ten subjects in whom 131I-apoA-IV-1 and 125I-apoA-IV-2 were simultaneously injected, the FCR of apoA-IV-2 was significantly slower by paired t test (P = 0.003). The FCR of apoA-IV-2 in an apoA-IV-2/2 homozygote was only 1.49 d-1, substantially slower than in all other subjects. We conclude that: (a) apoA-IV is a rapidly catabolized apolipoprotein in humans, with a fractional catabolic rate more than 10 times greater than that of apoA-I; (b) apoA-IV has a high absolute transport rate similar to that of apoA-I; (c) plasma levels of apoA-IV are primarily determined by apoA-IV production rate in normolipidemic subjects; and (d) the fractional catabolic rate of the common variant apoA-IV-2 is slower than that of the wild-type apoA-IV-1.
authors.affiliation: Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: D J
authors.initials: DJ
authors.lastname: Rader
authors.forename: J
authors.initials: J
authors.lastname: Schäfer
authors.forename: P
authors.initials: P
authors.lastname: Lohse
authors.forename: B
authors.initials: B
authors.lastname: Verges
authors.forename: M
authors.initials: M
authors.lastname: Kindt
authors.forename: L A
authors.initials: LA
authors.lastname: Zech
authors.forename: A
authors.initials: A
authors.lastname: Steinmetz
authors.forename: H B
authors.initials: HB
authors.lastname: Brewer
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000302:isolation & purification / Q000378:metabolism; D001054:Apolipoproteins A / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D002846:Chromatography, Affinity; D002850:Chromatography, Gel; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D010641:Phenotype; D011865:Radioisotope Dilution Technique; D013997:Time Factors
chemical_list: D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D007457:Iodine Radioisotopes; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; C022205:apolipoprotein A-IV