A novel role for GalNAc-T2 dependent glycosylation in energy homeostasis - Nantes Université Access content directly
Journal Articles Molecular metabolism Year : 2022

A novel role for GalNAc-T2 dependent glycosylation in energy homeostasis

Cristy R.C. Verzijl
  • Function : Author
Federico Oldoni
  • Function : Author
Natalia Loaiza
  • Function : Author
Justina Wolters
  • Function : Author
E. Tian
  • Function : Author
Weiming Yang
  • Function : Author
Dicky Struik
  • Function : Author
Marieke Smit
  • Function : Author
Niels Kloosterhuis
  • Function : Author
Amy Fernandez
  • Function : Author
Nadine Samara
  • Function : Author
Kelly ten Hagen
  • Function : Author
Kruti Dalal
  • Function : Author
Aliona Chernish
  • Function : Author
Peggy Mccluggage
  • Function : Author
Lawrence Tabak
  • Function : Author
Johan Jonker
  • Function : Author
Jan Albert Kuivenhoven
  • Function : Author

Abstract

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25 , are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25 , overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. Conclusions: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.

Dates and versions

hal-04060053 , version 1 (05-04-2023)

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Cristy R.C. Verzijl, Federico Oldoni, Natalia Loaiza, Justina Wolters, Antoine Rimbert, et al.. A novel role for GalNAc-T2 dependent glycosylation in energy homeostasis. Molecular metabolism, 2022, 60 (1), pp.101472. ⟨10.1016/j.molmet.2022.101472⟩. ⟨hal-04060053⟩
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