1. Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans
- Author
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Erin M. Foley, Michiel A. J. van de Sande, Julia J. Witjes, Michael W.T. Tanck, J. Han M. Levels, Philip L.S.M. Gordts, Erik S.G. Stroes, Max Nieuwdorp, Marjolein A.W. van den Boogert, Geesje M. Dallinga-Thie, Jeff Esko, Kristin I. Stanford, H. Carlijne Hassing, Hans L. Mooij, Sophie J. Bernelot Moens, John J.P. Kastelein, Internal medicine, ICaR - Circulation and metabolism, Other departments, 01 Internal and external specialisms, Graduate School, Amsterdam Cardiovascular Sciences, Cardiology, Amsterdam Public Health, Epidemiology and Data Science, Amsterdam institute for Infection and Immunity, Experimental Vascular Medicine, Vascular Medicine, and Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
Adult ,Male ,medicine.medical_specialty ,Heterozygote ,multiple exostoses ,Biochemistry & Molecular Biology ,Multiple Sclerosis ,Knockout ,QD415-436 ,Familial hypercholesterolemia ,Biology ,Medical Biochemistry and Metabolomics ,Compound heterozygosity ,N-Acetylglucosaminyltransferases ,Cardiovascular ,Biochemistry ,chemistry.chemical_compound ,Mice ,Endocrinology ,Internal medicine ,Retinyl palmitate ,medicine ,Animals ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,triglycerides ,Mice, Knockout ,familial hypercholesterolemia ,Area under the curve ,Cell Biology ,Middle Aged ,hereditary multiple exostoses ,medicine.disease ,Postprandial Period ,Postprandial ,Heart Disease ,chemistry ,LDL receptor ,Mutation ,heparan sulfates ,Female ,Biochemistry and Cell Biology ,Patient-Oriented and Epidemiological Research ,hereditary ,Chylomicron ,Lipoprotein - 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
- Published
- 2015