HDLs in apoA-I transgenic Abca1 knockout mice are remodeled normally in plasma but are hypercatabolized by the kidney

Lee, Ji-Young; Timmins, Jenelle M.; Mulya, Anny; Smith, Thomas L.; Zhu, Yiwen; Rubin, Edward M.; Chisholm, Jeffrey W.; Colvin, Perry L.; Parks, John S.

doi:10.1194/jlr.m500179-jlr200

Cited by 31 publications

(25 citation statements)

References 69 publications

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“…6); however, LCAT activity was not necessary for remodeling. A similar conclusion was reached in our previous study, in which in vitro remodeling of plasma isolated pre-b HDLs, which were similar in size and composition to the pre-b1 HDLs in this study, occurred unabated in the presence of an LCAT inhibitor (35). These data do not contradict the essential role for LCAT in the maturation of nascent discoidal preb HDLs to spherical plasma HDLs through cholesterol esterification (52)(53)(54)(55).…”

Section: Discussionsupporting

confidence: 70%

“…For all tracers, the injected apoA-I tracer mass was about 5 mg per animal (3 3 10 5 cpm per mouse/6 3 10 4 cpm/mg 5 5 mg/mouse) and represented approximately 0.17% of the total plasma apoA-I mass in hA-I Tg mice (plasma apoA-I pool size 5 ?3,000 mg) (35). Plasma was drawn from recipient mice at the indicated times to determine the kinetics of turnover of the tracers in the circulation.…”

Section: Preparation Of Nascent Pre-b Hdl Tracermentioning

confidence: 99%

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

Mulya

Lee

Gebre

et al. 2008

Journal of Lipid Research

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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

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Section: Discussionsupporting

confidence: 70%

Section: Preparation Of Nascent Pre-b Hdl Tracermentioning

confidence: 99%

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

Mulya

Lee

Gebre

et al. 2008

Journal of Lipid Research

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“…It appears likely that APOL1 protein in podocytes is predominantly locally synthesized ( 4,5 ). A considerable amount of HDL APOA1 is catabolized in the kidney in human APOA1 transgenic mice and nonhuman primates ( 32,33 ). APOL1 ( 5 ), APOA1, and HPR proteins are present in renal tubule cells, but not glomeruli, whereas HPR and APOA1 mRNAs are absent in glomeruli (data not shown).…”

Section: Discussionmentioning

confidence: 95%

Characterization of circulating APOL1 protein complexes in African Americans

Weckerle

Snipes

Cheng

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org G1 and G2 renal-risk variants on chromosome 22q13.1 ( 1-3 ). Although APOL1 mRNA and APOL1 protein are present in human kidney ( 4, 5 ), the major APOL1 reservoir appears to be circulating protein ( 5, 6 ). APOL1 was initially discovered as a minor apolipoprotein of plasma HDLs ( 6 ); however, its distribution among HDL subfractions has not been well-defi ned. APOL1 nephropathy variants associate with HDL subfraction concentrations ( 7 ) and CVD risk, although controversial results have been reported with CVD ( 8-11 ). Trypanosome lytic factors (TLF1 and TLF2) contain APOL1 protein ( 12 ) and are minor HDL subfractions in humans that contribute to innate immunity via protection from infection, including from African trypanosomes ( 13 ).Association was not observed between plasma APOL1 concentrations and APOL1 genotype in African Americans with treated HIV infection; plasma APOL1 levels also did not associate with the risk of HIV-associated nephropathy or chronic kidney disease ( 14 ). Whether serum APOL1 protein levels and their distribution among HDL particles are associated with APOL1 genotypes in healthy individuals is unknown. Because free APOL1 protein may be taken up by podocytes in vitro ( 5 ), it remains critical to determine whether serum APOL1 concentrations or the structure/composition of variant APOL1 proteins and their associated complexes are specifi c to the G1 and G2 renalrisk variants, relative to nonrisk G0.To address these issues, serum APOL1 protein levels and size distribution were examined in age-and gender-matched African Americans without kidney disease based on APOL1 genotype using fast protein LC (FPLC) and immunoblot analysis. Proteomics analysis was performed to compare the composition of APOL1 protein-containing complexes. These Abstract APOL1 gene renal-risk variants are associated with nephropathy and CVD in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from nonrisk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two nonoverlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter). Neither of these protein complexes associated with HDL or LDL. Proteomic analysis revealed that complex A was composed of APOA1, haptoglobin-related protein (HPR), and complement C3, whereas complex B contained APOA1, HPR, IgM, and fibronectin. Serum HPR was less abundant on complex B in individuals with G1 and G2 renal-risk variant genotypes, relative to G0 ( P = 0.0002-0.037). These circulating complexes may play roles in HDL metabolism and susceptibility to CVD. A major breakthrough in human molecular genetics was identifi cation of the powerful contribution of APOL1 gene ...

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“…In the case of apoA-I, clearance occurs mainly in the kidney and liver. Lipid-free/lipid-poor apoA-I particles are the preferred substrate for apoA-I uptake into the kidney (62), where it is filtered and then absorbed in kidney proximal tubules through the action of cubilin, a receptor for intrinsic factor-vitamin B12, with megalin serving as a coreceptor (63)(64)(65). A number of HDL-modifying processes can potentially generate small lipid-free/lipid-poor apoA-I particles.…”

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confidence: 99%

Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice

Kim

Beer

Wroblewski

et al. 2016

Journal of Lipid Research

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HDLs in apoA-I transgenic Abca1 knockout mice are remodeled normally in plasma but are hypercatabolized by the kidney

Cited by 31 publications

References 69 publications

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

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

Characterization of circulating APOL1 protein complexes in African Americans

Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice

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