The effects of apolipoprotein B depletion on HDL subspecies composition and function

Davidson, W. Sean; Heink, Anna; Sexmith, Hannah; Melchior, John T.; Gordon, Scott M.; Kuklenyik, Zsuzsanna; Woollett, Laura A.; Barr, John R.; Jones, Jeffrey I.; Toth, Christopher; Shah, Amy S.

doi:10.1194/jlr.m066613

Cited by 56 publications

(58 citation statements)

References 39 publications

(47 reference statements)

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“…Parallel studies of the transfer of native human HDL-[ 3 H]FC to serum gave remarkably similar results with the majority of HDL-[ 3 H]FC transferring to LDL within 2 h (Supplementary Figure I). Given time limitations of SEC, the kinetics of nHDL-[ 3 H]FC transfer to LDL were determined by heparin-Mn +2 precipitation of LDL 15,16 after its incubation with nHDL-[ 3 H]FC at 37° C for various times; the halftime for this process was 2.1 ± 0.5 min (Figure 2E). Notably, transfer of nHDL- and HDL-FC to LDL occurred over a time frame in which less than 5% of nHDL- and HDL-[ 3 H]FC are converted to CE by mouse plasma LCAT activity (Supplementary Figure II).…”

Section: Resultsmentioning

confidence: 99%

ABCA1-Derived Nascent High-Density Lipoprotein–Apolipoprotein AI and Lipids Metabolically Segregate

Gillard

Gotto

et al. 2017

ATVB

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Objective Reverse cholesterol transport (RCT) comprises cholesterol efflux from ABCA1-expressing macrophages to apo AI giving nascent high density lipoprotein (nHDL), esterification of nHDL-free cholesterol (FC), selective hepatic extraction of HDL-lipids, and hepatic conversion of HDL-cholesterol to bile salts, which are excreted. We tested this model by identifying the fates of nHDL-[3H]FC, [14C]PL, and [125I]apo AI in serum in vitro and in vivo. Approach and Results During in vitro incubation of human serum, nHDL-[3H]FC and [14C]PL rapidly transfer to HDL and low density lipoproteins (LDL; t1/2 = 2–7 min) while nHDL-[125I]apo AI transfers solely to HDL (t1/2<10 min) and to the lipid-free form (t1/2 >480 min). Following injection into mice nHDL-[3H]FC and [14C]PL rapidly transfer to liver (t1/2 ~ 2–3 min) whereas apo AI clears with t1/2 = ~460 min. The plasma nHDL-[3H]FC esterification rate is slow (0.46%/h) compared to hepatic uptake. Phospholipid transfer protein enhances nHDL-[14C]PL but not nHDL-[3H]FC transfer to cultured Huh7 hepatocytes. Conclusions nHDL-FC, PL, and apo AI enter different pathways in vivo. Most nHDL-[3H]FC and [14C]PL are rapidly extracted by the liver via scavenger receptor class B member 1 and spontaneous transfer; hepatic PL uptake is promoted by phospholipid transfer protein. nHDL-[125I]apo AI transfers to HDL and to the lipid-free form that can be recycled to nHDL formation. Cholesterol esterification by LCAT is a minor process in nHDL metabolism. These findings could guide the design of therapies that better mobilize peripheral tissue-FC to hepatic disposal.

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Section: Resultsmentioning

confidence: 99%

ABCA1-Derived Nascent High-Density Lipoprotein–Apolipoprotein AI and Lipids Metabolically Segregate

Gillard

Gotto

et al. 2017

ATVB

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“…After Roux-en-Y gastric bypass, studies in adults have shown the appearance of large, lipid-rich particles (either alpha-1 particles by 2D gel electrophoresis (26, 33) or HDL2 isolated by ultracentrifugation (25)). We chose to study HDL subpopulations using gel filtration chromatography over the former methods because in addition to allowing the recovery of the particles for functional analysis (23), it is performed at physiological pH and ionic strength without high g-forces resulting in significantly less proteome rearrangement compared to ultracentrifugation (34). We show that large atheroprotective HDL particles increase after VSG.…”

Section: Discussionmentioning

confidence: 99%

“…Given we have previously shown that the majority of cholesterol efflux occurs between fractions 20–25 (23), only these fractions were evaluated. Efflux across HDL fractions and subsequent mass spectrometry (MS) analysis was performed on a subset of n=6 individuals due to unavailable sample on n=4.…”

Section: Methodsmentioning

confidence: 99%

Weight loss surgery in adolescents corrects high-density lipoprotein subspecies and their function

et al. 2016

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Background/ObjectiveYouth with obesity have an altered HDL subspecies profile characterized by depletion of large apoE rich HDL particles and an enrichment of small HDL particles. The goal of this study was to test the hypothesis that this atherogenic HDL profile would be reversed and that HDL function would improve with metabolic surgery.MethodsSerum samples from adolescent males with severe obesity mean ± SD age of 17.4 ± 1.6 years were studied at baseline and 1 year following vertical sleeve gastrectomy (VSG). HDL subspecies and HDL function were evaluated pre and post VSG using paired t-tests. A lean group of adolescents was included as a reference group.ResultsAfter VSG, BMI decreased by 32% and insulin resistance as estimated by HOMA-IR decreased by 75% (both p<0.01). Large apoE rich HDL subspecies increased following VSG (p<0.01) and approached that of lean adolescents despite participants with considerable residual obesity. Additionally, HDL function improved compared to baseline (cholesterol efflux capacity increased by 12%, HDL lipid peroxidation potential decreased by 30%, and HDL anti-oxidative capacity improved by 25%, all p<0.01).ConclusionsMetabolic surgery results in a significant improvement in the quantity of large HDL subspecies and HDL function. Our data suggest metabolic surgery may improve cardiovascular risk in adolescents and young adults.

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“…Separating different subclasses from blood plasma is an important step for understanding the correlation between specific lipoprotein characteristics and disease. [4]…”

Section: Introductionmentioning

confidence: 99%

Asymmetrical flow field-flow fractionation for improved characterization of human plasma lipoproteins

et al. 2018

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High and low-density lipoproteins (HDL and LDL) are attractive targets for biomarker discovery. However, ultracentrifugation (UC), the current methodology of choice for isolating HDL and LDL is tedious, requires large sample volume, results in sample loss, and does not readily provide information on particle size. In this work, human plasma HDL and LDL are separated and collected using semi-preparative asymmetrical flow field-flow fractionation (SPAF4) and UC. The SP-AF4 and UC separation conditions, sample throughput, and liquid chromatography/mass spectrometry (LC/MS) lipidomic results are compared. Over 600 μg of total proteins are recovered in a single SP-AF4 run and Western blot results confirm apoA1 pure and apoB100 pure fractions, consistent with HDL and LDL, respectively. The SP-AF4 separation requires ~60 minutes per sample, thus providing a marked improvement over UC which can span hours to days. Lipidome analysis of SP-AF4 prepared HDL and LDL fractions are compared to UC prepared HDL and LDL samples. Over 270 lipids in positive MS mode and over 140 lipids in negative MS mode are identified by both sample preparation techniques with over 98% overlap between the lipidome. Additionally, lipoprotein size distributions are determined using analytical scale AF4 coupled with multiangle light scattering (MALS) and dynamic light scattering (DLS) detectors. These developments position SP-AF4 as a sample preparation method of choice for lipoprotein biomarker characterization and identification.

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The effects of apolipoprotein B depletion on HDL subspecies composition and function

Cited by 56 publications

References 39 publications

ABCA1-Derived Nascent High-Density Lipoprotein–Apolipoprotein AI and Lipids Metabolically Segregate

ABCA1-Derived Nascent High-Density Lipoprotein–Apolipoprotein AI and Lipids Metabolically Segregate

Weight loss surgery in adolescents corrects high-density lipoprotein subspecies and their function

Asymmetrical flow field-flow fractionation for improved characterization of human plasma lipoproteins

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