Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents

Khetarpal SA, Schjoldager KT, Christoffersen C, Raghavan A, Edmondson AC, Reutter HM, Ahmed B, Ouazzani R, Peloso GM, Vitali C, Zhao W, Somasundara AVH, Millar JS, Park Y, Fernando G, Livanov V, Choi S, Noe E, Patel P, Ho SP, Kirchgessner TG, Wandall HH, Hansen L, Bennett EP, Vakhrushev SY, Saleheen D, Kathiresan S, Brown CD, Abou Jamra R, Leguern E, Clausen H, Rader DJ (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Cell Metabolism Elsevier (Cell Press)

Book Volume: 24

Pages Range: 234-45

Journal Issue: 2

DOI: 10.1016/j.cmet.2016.07.012

Abstract

Human 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.

Authors with CRIS profile

Heiko Martin Reutter

Additional Organisation(s)

Institute of Human Genetics

Involved external institutions

University of Copenhagen DK Denmark (DK) University of Pennsylvania (UPenn) US United States (USA) (US) University of Paris 6 - Pierre et Marie Curie / Université Paris VI Pierre et Marie Curie (UPMC) FR France (FR) Universität Leipzig DE Germany (DE) Massachusetts General Hospital US United States (USA) (US) University of Cambridge GB United Kingdom (GB) Bristol-Myers Squibb US United States (USA) (US) Gachon University KR Korea, Republic of (KR) Centre Hospitalo-Universitaire Ibn Sina de Rabat (CHUIS) MA Morocco (MA) Mohammed V University (UMVA) / جامعة محمد الخامس‎ MA Morocco (MA) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE)

How to cite

APA:

Khetarpal, S.A., Schjoldager, K.T., Christoffersen, C., Raghavan, A., Edmondson, A.C., Reutter, H.M.,... Rader, D.J. (2016). Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents. Cell Metabolism, 24(2), 234-45. https://doi.org/10.1016/j.cmet.2016.07.012

MLA:

Khetarpal, Sumeet A., et al. "Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents." Cell Metabolism 24.2 (2016): 234-45.

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