Marjolein A W van den Boogert1,2, Lars E Larsen2,3, Lubna Ali2, Sacha D Kuil4, Patrick L W Chong2,3, Anke Loregger5, Jeffrey Kroon1,2, Johan G Schnitzler2, Alinda W M Schimmel2, Jorge Peter2, Johannes H M Levels2, Gerry Steenbergen4, Eva Morava6, Geesje M Dallinga-Thie1,2, Ron A Wevers4, Jan Albert Kuivenhoven7, Nicholas J Hand3, Noam Zelcer5, Daniel J Rader3, Erik S G Stroes1, Dirk J Lefeber4,8, Adriaan G Holleboom1. 1. Departments of Vascular Medicine (M.A.W.v.d.B., J.K., G.M.D.-T., E.S.G.S., A.G.H.), Amsterdam University Medical Centers, location AMC, The Netherlands. 2. Experimental Vascular Medicine (M.A.W.v.d.B., L.E.L., L.A., P.L.W.C., J.K., J.G.S., A.W.M.S., J.P., J.H.M.L., G.M.D.-T.), Amsterdam University Medical Centers, location AMC, The Netherlands. 3. Department of Genetics and Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (L.E.L., P.L.W.C., N.J.H., D.J.R.). 4. Department of Laboratory Medicine, Translational Metabolic Laboratory (S.D.K., G.S., R.A.W., D.J.L.), Radboud University Medical Center, Nijmegen, The Netherlands. 5. Medical Biochemistry (A.L., N.Z.), Amsterdam University Medical Centers, location AMC, The Netherlands. 6. Department of Clinical Genomics, Mayo Clinic, Rochester, MN (E.M.). 7. Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, The Netherlands (J.A.K.). 8. Department of Neurology (D.J.L.), Radboud University Medical Center, Nijmegen, The Netherlands.
Abstract
BACKGROUND: The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDGs) with defective N-glycosylation. METHODS: We studied 29 patients with the 2 most prevalent types of type I CDG, ALG6 (asparagine-linked glycosylation protein 6)-deficiency CDG and PMM2 (phosphomannomutase 2)-deficiency CDG, and 23 first- and second-degree relatives with a heterozygous mutation and measured plasma cholesterol levels. Low-density lipoprotein (LDL) metabolism was studied in 3 cell models-gene silencing in HepG2 cells, patient fibroblasts, and patient hepatocyte-like cells derived from induced pluripotent stem cells-by measuring apolipoprotein B production and secretion, LDL receptor expression and membrane abundance, and LDL particle uptake. Furthermore, SREBP2 (sterol regulatory element-binding protein 2) protein expression and activation and endoplasmic reticulum stress markers were studied. RESULTS: We report hypobetalipoproteinemia (LDL cholesterol [LDL-C] and apolipoprotein B below the fifth percentile) in a large cohort of patients with type I CDG (mean age, 9 years), together with reduced LDL-C and apolipoprotein B in clinically unaffected heterozygous relatives (mean age, 46 years), compared with 2 separate sets of age- and sex-matched control subjects. ALG6 and PMM2 deficiency led to markedly increased LDL uptake as a result of increased cell surface LDL receptor abundance. Mechanistically, this outcome was driven by increased SREBP2 protein expression accompanied by amplified target gene expression, resulting in higher LDL receptor protein levels. Endoplasmic reticulum stress was not found to be a major mediator. CONCLUSIONS: Our study establishes N-glycosylation as an important regulator of LDL metabolism. Given that LDL-C was also reduced in a group of clinically unaffected heterozygotes, we propose that increasing LDL receptor-mediated cholesterol clearance by targeting N-glycosylation in the LDL pathway may represent a novel therapeutic strategy to reduce LDL-C and cardiovascular disease.
BACKGROUND: The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDGs) with defective N-glycosylation. METHODS: We studied 29 patients with the 2 most prevalent types of type I CDG, ALG6 (asparagine-linked glycosylation protein 6)-deficiency CDG and PMM2 (phosphomannomutase 2)-deficiency CDG, and 23 first- and second-degree relatives with a heterozygous mutation and measured plasma cholesterol levels. Low-density lipoprotein (LDL) metabolism was studied in 3 cell models-gene silencing in HepG2 cells, patient fibroblasts, and patient hepatocyte-like cells derived from induced pluripotent stem cells-by measuring apolipoprotein B production and secretion, LDL receptor expression and membrane abundance, and LDL particle uptake. Furthermore, SREBP2 (sterol regulatory element-binding protein 2) protein expression and activation and endoplasmic reticulum stress markers were studied. RESULTS: We report hypobetalipoproteinemia (LDL cholesterol [LDL-C] and apolipoprotein B below the fifth percentile) in a large cohort of patients with type I CDG (mean age, 9 years), together with reduced LDL-C and apolipoprotein B in clinically unaffected heterozygous relatives (mean age, 46 years), compared with 2 separate sets of age- and sex-matched control subjects. ALG6 and PMM2 deficiency led to markedly increased LDL uptake as a result of increased cell surface LDL receptor abundance. Mechanistically, this outcome was driven by increased SREBP2 protein expression accompanied by amplified target gene expression, resulting in higher LDL receptor protein levels. Endoplasmic reticulum stress was not found to be a major mediator. CONCLUSIONS: Our study establishes N-glycosylation as an important regulator of LDL metabolism. Given that LDL-C was also reduced in a group of clinically unaffected heterozygotes, we propose that increasing LDL receptor-mediated cholesterol clearance by targeting N-glycosylation in the LDL pathway may represent a novel therapeutic strategy to reduce LDL-C and cardiovascular disease.
Entities:
Keywords:
cholesterol; congenital disorders of glycosylation; glycosylation; hypobetalipoproteinemias; receptors, LDL; sterol regulatory element binding protein 2
Authors: Julien H Park; Robert G Mealer; Abdallah F Elias; Susanne Hoffmann; Marianne Grüneberg; Saskia Biskup; Manfred Fobker; Jaclyn Haven; Ute Mangels; Janine Reunert; Stephan Rust; Jonathan Schoof; Corbin Schwanke; Jordan W Smoller; Richard D Cummings; Thorsten Marquardt Journal: J Inherit Metab Dis Date: 2020-09-14 Impact factor: 4.982
Authors: Hind Alsharhan; Bobby G Ng; Earnest James Paul Daniel; Jennifer Friedman; Eniko K Pivnick; Amal Al-Hashem; Eissa Ali Faqeih; Pengfei Liu; Nicole M Engelhardt; Kierstin N Keller; Jie Chen; Pamela A Mazzeo; Jill A Rosenfeld; Michael J Bamshad; Deborah A Nickerson; Kimiyo M Raymond; Hudson H Freeze; Miao He; Andrew C Edmondson; Christina Lam Journal: J Inherit Metab Dis Date: 2021-03-01 Impact factor: 4.750
Authors: Roubi Abuobeid; Javier Sánchez-Marco; María J Felices; Carmen Arnal; Juan Carlos Burillo; Roberto Lasheras; Rebeca Busto; Miguel A Lasunción; María Jesús Rodríguez-Yoldi; Roberto Martínez-Beamonte; Jesús Osada Journal: Int J Mol Sci Date: 2022-04-10 Impact factor: 6.208
Authors: Marjolein A W van den Boogert; Cleo L Crunelle; Lubna Ali; Lars E Larsen; Sacha D Kuil; Johannes H M Levels; Alinda W M Schimmel; Vassiliki Konstantopoulou; Maryse Guerin; Jan Albert Kuivenhoven; Geesje M Dallinga-Thie; Erik S G Stroes; Dirk J Lefeber; Adriaan G Holleboom Journal: J Inherit Metab Dis Date: 2019-12-29 Impact factor: 4.982