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

Journal of lipid research (2015-01-09)
Hans L Mooij, Sophie J Bernelot Moens, Philip L S M Gordts, Kristin I Stanford, Erin M Foley, Marjolein A W van den Boogert, Julia J Witjes, H Carlijne Hassing, Michael W Tanck, Michiel A J van de Sande, J Han Levels, John J P Kastelein, Erik S G Stroes, Geesje M Dallinga-Thie, Jeff D Esko, Max Nieuwdorp
ABSTRACT

Elevated nonfasting TG-rich lipoprotein levels are a risk factor for CVD. To further evaluate the relevance of LDL-receptor (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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cholesterol, Sigma Grade, ≥99%
Sigma-Aldrich
Cholesterol, powder, BioReagent, suitable for cell culture, ≥99%
Supelco
Retinyl Palmitate (Vitamin A Palmitate), Pharmaceutical Secondary Standard; Certified Reference Material
SAFC
Cholesterol, Plant-Derived
Sigma-Aldrich
SyntheChol® NS0 Supplement, 500 ×, synthetic cholesterol, animal component-free, aqueous solution, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Cholesterol, from sheep wool, ≥92.5% (GC), powder
Supelco
Cholesterol, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Retinyl palmitate, potency: ≥1,700,000 USP units per g
Sigma-Aldrich
Retinyl palmitate, Type IV, ~1,800,000 USP units/g, oil
Cholesterol, European Pharmacopoeia (EP) Reference Standard
USP
Retinyl palmitate, United States Pharmacopeia (USP) Reference Standard
SAFC
Cholesterol, from sheep wool, Controlled origin, meets USP/NF testing specifications
Supelco
Cholesterol solution, certified reference material, 10 mg/mL in chloroform