Initial interaction of apoA-I with ABCA1 impacts in vivo metabolic fate of nascent HDL

Abstract

We investigated the in vivo metabolic fate of preb HDL particles in human apolipoprotein A-I transgenic (hA-I Tg ) mice. Pre-b HDL tracers were assembled by incubation of [125 I]tyramine cellobiose-labeled apolipoprotein A-I (apoA-I) with HEK293 cells expressing ABCA1. Radiolabeled pre-b HDLs of increasing size (pre-b1, -2, -3, and -4 HDLs) were isolated by fast-protein liquid chromatography and injected into hA-I Tg -recipient mice, after which plasma decay, in vivo remodeling, and tissue uptake were monitored. Pre-b2, -3, and -4 had similar plasma die-away rates, whereas pre-b1 HDL was removed 7-fold more rapidly. Radiolabel recovered in liver and kidney 24 h after tracer injection suggested increased (P , 0.001) liver and decreased kidney catabolism as pre-b HDL size increased. In plasma, pre-b1 and -2 were rapidly (,5 min) remodeled into larger HDLs, whereas pre-b3 and -4 were remodeled into smaller HDLs. Pre-b HDLs were similarly remodeled in vitro with control or LCAT-immunodepleted plasma, but not when incubated with phospholipid transfer protein knockout plasma. Our results suggest that initial interaction of apoA-I with ABCA1 imparts a unique conformation that partially determines the in vivo metabolic fate of apoA-I, resulting in increased liver and decreased kidney catabolism as pre-b HDL particle size

A novel role for ABCA1-generated large pre- migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion

“…content ( 8 ). A similar size range of nascent HDL particles was also observed when apoA-I was incubated with McA cells ( 11 ). We hypothesized that silencing of ABCA1 in McA cells results in reduced nascent HDL formation that normally attenuates VLDL TG secretion via a PI3 kinase signaling pathway, resulting in increased VLDL TG secretion.…”

“…In addition, McA cells incubated with apoA-I assemble nascent HDL particles that are similar in size to the discrete-sized populations of nascent HDL assembled by HEK293 cells expressing ABCA1 ( 11 ).…”

Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells

“…The initial lipidation of newly secreted apoA-I by phospholipids and cholesterol, mainly promoted by the membrane protein ABCA1 activity at the cell surface, is critical during the early formation of HDL particles, and for stabilizing apoA-I as biologically active molecules (23)(24)(25)(26). There is a signifi cant link between the ABCA1-mediated cholesterol effl ux in the initial formation of HDL and with its stability in plasma (24)(25)(26)(27). Liver-specifi c inactivation of ABCA1 in mice resulted in a 2-fold increase in the catabolic rate of HDL protein ( 27 ).…”

Analysis of lipid transfer activity between model nascent HDL particles and plasma lipoproteins: implications for current concepts of nascent HDL maturation and genesis

“…Previously, we used these model nascent particles to examine their cholesterol esterifi cation kinetics ( 11 ), and more recently, similar particles were used to investigate their in vivo metabolic fate in human apoA-I transgenic mice ( 12 ).…”