N-Glycosylation Defects in Man Lower LDL-Cholesterol Through Increased LDL Receptor Expression.

A new interesting article has been published in Circulation. 2019 May 23. doi: 10.1161/CIRCULATIONAHA.118.036484. and titled:

N-Glycosylation Defects in Man Lower LDL-Cholesterol Through Increased LDL Receptor Expression.

Authors of this article are:

van den Boogert MAW, Larsen LE, Ali L, Kuil SD, Chong PLW, Loregger A, Kroon J, Schnitzler JG, Schimmel AWM, Peter J, Levels JHM, Steenbergen G, Morava E, Dallinga-Thie GM, Wevers RA, Kuivenhoven JA, Hand NJ, Zelcer N, Rader DJ, Stroes ESG, Lefeber DJ, Holleboom AG.

A summary of the article is shown below:

BACKGROUND: The importance of protein glycosylation in regulating lipid metabolism is increasingly becoming apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDG-I) with defective N-glycosylation.METHODS: We studied 29 patients of the two most prevalent types of CDG-I: ALG6- and PMM2-CDG, and 23 first- and second-degree relatives with a heterozygote mutation and measured plasma cholesterol levels. LDL metabolism was studied in three cell models – gene silencing in HepG2 cells; patient fibroblasts; patient hepatocyte-like cells derived from induced pluripotent stem cells – by measuring apolipoprotein B (apoB) production and secretion, LDL receptor (LDLR) expression and membrane abundance, and LDL particle uptake. Furthermore, SREBP2 protein expression and activation, as well as ER stress markers were studied.RESULTS: We report hypobetalipoproteinemia (LDL-cholesterol (LDL-c) and apoB below the 5th percentile) in a large cohort of CDG-I patients (mean age: 9 years), together with reduced LDL-c and apoB in clinically unaffected heterozygous relatives (mean age: 46 years), compared to two separate sets of age- and gender-matched controls. ALG6 and PMM2 deficiency led to markedly increased LDL uptake due to increased cell surface LDLR abundance. Mechanistically, this outcome was driven by increased SREBP2 protein expression accompanied by amplified target gene expression resulting in higher LDLR protein levels. ER 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 LDLR-mediated cholesterol clearance by targeting N-glycosylation in the LDL pathway may represent a novel therapeutic strategy to reduce LDL-c and cardiovascular disease.

Check out the article’s website on Pubmed for more information:

This article is a good source of information and a good way to become familiar with topics such as: ALG6; CDG; Hypobetalipoproteinemia; PMM2; glycosylation.