N-Glycosylation Defects in Humans Lower Low-Density Lipoprotein Cholesterol Through Increased Low-Density Lipoprotein Receptor Expression.

Child Cholesterol, LDL / genetics Female Glycosylation Humans Male Receptors, LDL / metabolism
cholesterol congenital disorders of glycosylation glycosylation hypobetalipoproteinemias receptors, LDL sterol regulatory element binding protein 2

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
23 07 2019
Historique:
pubmed: 24 5 2019
medline: 15 4 2020
entrez: 24 5 2019
Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.118.036484 PMID: 31117816
pubmed: 31117816
doi: 10.1161/CIRCULATIONAHA.118.036484
doi:

Substances chimiques

Cholesterol, LDL 0
Receptors, LDL 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

280-292

Auteurs

Marjolein A W van den Boogert (MAW)

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.
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.

Lars E Larsen (LE)

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.
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.).

Lubna Ali (L)

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.

Sacha D Kuil (SD)

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.

Patrick L W Chong (PLW)

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.
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.).

Anke Loregger (A)

Medical Biochemistry (A.L., N.Z.), Amsterdam University Medical Centers, location AMC, The Netherlands.

Jeffrey Kroon (J)

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.
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.

Johan G Schnitzler (JG)

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.

Alinda W M Schimmel (AWM)

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.

Jorge Peter (J)

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.

Johannes H M Levels (JHM)

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.

Gerry Steenbergen (G)

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.

Eva Morava (E)

Department of Clinical Genomics, Mayo Clinic, Rochester, MN (E.M.).

Geesje M Dallinga-Thie (GM)

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.
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.

Ron A Wevers (RA)

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.

Jan Albert Kuivenhoven (JA)

Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, The Netherlands (J.A.K.).

Nicholas J Hand (NJ)

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.).

Noam Zelcer (N)

Medical Biochemistry (A.L., N.Z.), Amsterdam University Medical Centers, location AMC, The Netherlands.

Daniel J Rader (DJ)

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.).

Erik S G Stroes (ESG)

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.

Dirk J Lefeber (DJ)

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.
Department of Neurology (D.J.L.), Radboud University Medical Center, Nijmegen, The Netherlands.

Adriaan G Holleboom (AG)

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.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › N-Glycosylation Defects in Humans Lower...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Lipoprotéines LDL › Cholestérol LDL › N-Glycosylation Defects in Humans Lower...
questionsmedicales.fr › Métabolisme › Métabolisme glucidique › Glycosylation › N-Glycosylation Defects in Humans Lower...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › N-Glycosylation Defects in Humans Lower...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux lipoprotéines › Récepteurs aux lipoprotéines LDL › N-Glycosylation Defects in Humans Lower...