Journal
CELL METABOLISM
Volume 24, Issue 2, Pages 234-245Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2016.07.012
Keywords
-
Categories
Funding
- Danish Research Councils
- Kirsten og Freddy Johansen Fonden
- A.P. Moller og Hustru Chastine Mc-Kinney Mollers Fond til Almene Formaal
- Novo Nordisk Foundation
- University of Copenhagen [CDO2016]
- Danish National Research Foundation [DNRF107]
- NIH [R01 HL111398, R01 HL089309]
- Foundation Leducq [10CVD03]
- German Research Foundation (DFG) [AB393/2-2]
- Mizutani Foundation
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available