کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2792408 1155048 2016 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی علوم غدد
پیش نمایش صفحه اول مقاله
Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents
چکیده انگلیسی


• Genetic loss of function of GALNT2 lowers HDL-C in man, rodents, and nonhuman primates
• ANGPTL3 and ApoC-III are non-redundant targets of GalNAc-T2 in humans
• PLTP O-glycosylation by GalNAc-T2 potentiates its activity and raises HDL-C
• GALNT2 GWAS SNP alleles associated with lower HDL-C reduce hepatic GALNT2 expression

SummaryHuman genetics studies have implicated GALNT2, encoding GalNAc-T2, as a regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian models. We identified two humans homozygous for loss-of-function mutations in GALNT2 who demonstrated low HDL-C. We also found that GALNT2 loss of function in mice, rats, and nonhuman primates decreased HDL-C. O-glycoproteomics studies of a human GALNT2-deficient subject validated ANGPTL3 and ApoC-III as GalNAc-T2 targets. Additional glycoproteomics in rodents identified targets influencing HDL-C, including phospholipid transfer protein (PLTP). GALNT2 deficiency reduced plasma PLTP activity in humans and rodents, and in mice this was rescued by reconstitution of hepatic Galnt2. We also found that GALNT2 GWAS SNPs associated with reduced HDL-C also correlate with lower hepatic GALNT2 expression. These results posit GALNT2 as a direct modulator of HDL metabolism across mammals.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 24, Issue 2, 9 August 2016, Pages 234–245
نویسندگان
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