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A unique feature of APOA4 is that it is an intestinal apolipoprotein secreted on HDL and chylomicrons. The goal of this study was to gain a better understanding of the origin and function of APOA4 on HDL by studying its metabolism across 6 HDL sizes. Twelve participants completed a metabolic tracer study. HDL was isolated by APOA1 immunopurification and separated by size. Tracer enrichments for APOA4 and APOA1 were determined by targeted mass spectrometry, and metabolic rates were derived by compartmental modeling. APOA4 metabolism on small HDL (alpha3, prebeta, and very small prebeta) was distinct from that of APOA4 on large HDL (alpha0, 1, 2). APOA4 on small HDL appeared in circulation by 30 minutes and was relatively rapidly catabolized. In contrast, APOA4 on large HDL appeared in circulation later (1\u20132 hours) and had a much slower catabolism. The unique metabolic profiles of APOA4 on small and large HDL likely indicate that each has a distinct origin and function in humans. 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