Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans

Gonzales, Jon C.; Gordts, Philip L.S.M.; Foley, Erin M.; Esko, Jeffrey D.

doi:10.1172/jci67398

Cited by 67 publications

(62 citation statements)

References 70 publications

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“…An alternate mechanism based on interference with ApoB-48 recognition (37) could explain why ApoC-III reduces TRL clearance only in mice deficient in both LRP1 and LDLR. Interestingly, ApoC-III does not seem to interfere with clearance mediated by hepatic HSPG receptors, which occurs via binding of ApoE and ApoA-V to heparan sulfate (24). The accumulation of ApoC-III in TRLs from all mouse strains lacking N-deacetylase/N-sulfotransferase-1 (NDST1) (Supplemental Figure 8B) suggests the possibility that ApoC-III-bearing particles may be preferentially cleared through HSPG receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Post-heparin plasma was obtained from fasted mice 5 minutes after retro-orbital injection of 5 units per mouse of heparin. To measure total lipase activity, plasma samples were incubated with 10% Intralipid/[ 3 H]TG emulsion (Hospira) as a substrate and human serum as the source of ApoC-III (24). The contribution of hepatic lipase was determined by including 1 M NaCl in the assay, and the values were subtracted from the total lipase activity to estimate the activity attributed to LPL.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

Gordts¹,

Nock²,

Son³

et al. 2016

Journal of Clinical Investigation

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210

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

Gordts¹,

Nock²,

Son³

et al. 2016

Journal of Clinical Investigation

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215

210

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“…The presence of the LDL receptor binding domain facilitates the hepatic clearance of cholesteryl esters, resulting in a signifi cant decrease in plasma cholesterol ( 94 ). Unlike LDL, which is cleared by the LDL receptor, the apoE-containing lipoproteins can also be cleared by alternative receptors such as LDL receptor-related proteins (LRPs) and heparan sulfate proteoglycans (HSPGs) ( 95 ). Thus, apoE plays a prominent role in clearing apoB-containing lipoproteins such as chylomicrons, VLDL, and remnant lipoproteins, all of which can be pro-atherogenic.…”

Section: Anti-atherogenic Mechanisms Of Apoe Actionmentioning

confidence: 99%

Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review

White

Garber

Anantharamaiah

2014

Journal of Lipid Research

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“…The in vivo role of HSPGs in TRL clearance in mice was initially illustrated by injecting heparinase, a heparan sulfate degrading enzyme, into the portal vein, which resulted in decreased TRL clearance in mice ( 15 ). Subsequent genetic studies showed that syndecan-1 (Sdc1), a type of transmembrane HSPG that resides on the basal membrane of hepatocytes exposed to the Space of Disse, binds to TRLs by way of the sulfated heparan sulfate chains on the proteoglycan and apoE and apoAV on the TRL particles ( 16,17 ). Mutations affecting the biosynthesis of the heparan sulfate chains or in the expression of Sdc1 in murine models were invariably associated with delayed postprandial TRL clearance and validated the concept that Sdc1 and specifi c HSPG-sulfation patterns are critical determinants for murine hepatic TRL clearance ( 18,19 ).…”

Section: Vitamin a Fat Tolerance Testing In Micementioning

confidence: 99%

Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans

Mooij¹,

Moens²,

Gordts

et al. 2015

Journal of Lipid Research

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The presence of increased TGs, defi ned as plasma TG levels >1.7 mM (150 mg/dl), occurs in 10-20% of the population in Western countries and is associated with increased risk of CVD ( 1 ). The etiology of hypertriglyceridemia is complex, and current therapeutic strategies to lower TG levels, including fi brates, PUFAs, and statins are available, yet their effi cacy with regard to lower CVD risk is not fully elucidated. Hence, the need for identification and characterization of additional pathways controlling synthesis and clearance of triglyceride-rich lipo proteins (TRLs) is ongoing, aiming to identify selective and potent targets for interventions. Although TG levels are routinely measured in a fasting state, observational studies have substantiated that nonfasting TG levels are in fact superior in predicting CVD risk ( 1-6 ). In this regard, the most important players involved in hepatic removal of TRLs are the LDL receptor (LDLr), the LDL receptor related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) ( 7-9 ). Of note, heterozygous Abstract Elevated nonfasting TG-rich lipoprotein levels are a risk factor for CVD. To further evaluate the relevance of LDLreceptor (LDLr) pathway and heparan sulfate proteoglycans (HSPGs) in TG homeostasis, we analyzed fasting and postprandial TG levels in mice bearing combined heterozygous mutations in both Exostosin (Ext) 1 and Ldlr , in subjects with hereditary multiple exostosis (HME) due to a heterozygous loss-of-function mutation in EXT1 or EXT2 (N = 13), and in patients with heterozygous mutations in LDLR [familial hypercholesterolemia (FH)] and SNPs in major HSPG-related genes (n = 22). Mice bearing a homozygous mutation in hepatic Ext1 exhibited elevated plasma TGs similar to mice lacking other key enzymes involved in HSPG assembly. Compound heterozygous mice lacking Ldlr and Ext1 showed synergy on plasma TG accumulation and postprandial clearance. In human subjects, a trend was observed in HME patients toward reduced postprandial TG clearance with a concomitant reduction in chylomicron clearance [area under the curve (AUC)-retinyl ester (RE) HME, 844 ± 127 vs. controls, 646 ± 119 nM/h, P = 0.09]. Moreover, in FH subjects with a high HSPG gene score, retinyl palmitate excursions were higher (AUC-RE, 2,377 ± 293 vs. 1,565 ± 181 nM/h, P < 0.05). Incremental AUC-apoB48 was similar between the groups. In conclusion, the data are supportive for a minor yet additive role of HSPG in human postprandial TG clearance, and further studies are warranted. -Mooij, H.

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Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans

Cited by 67 publications

References 70 publications

ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review

Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans

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