Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from Fabry mice

Xing Li Meng, Taniqua S. Day, Nathan McNeill, Paula Ashcraft, Thomas Frischmuth, Seng H. Cheng, Zhi Ping Liu, Jin Song Shen, Raphael Schiffmann

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Fabry disease is caused by deficient activity of α-galactosidase A and subsequent intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Vascular endothelial cells may play important roles in disease pathogenesis, and are one of the main target cell types in therapeutic interventions. In this study, we generated immortalized aortic endothelial cell lines from a mouse model of Fabry disease. These cells retained endothelial cell-specific markers and functions. Gb3 expression level in one of these clones (referred to as FMEC2) was highly susceptible to culture media, and appeared to be regulated by glucosylceramide synthase. Results also showed that Gb3 could be upregulated by hydrocortisone. FMEC2 express the mannose 6-phosphate receptor and sortilin but not the mannose receptor. Uptake studies suggested that sortilin plays a role in the binding and internalization of mammalian cell-produced α-galactosidase A. Moss-aGal (a plant-made enzyme) was endocytosed by FMEC2 via a receptor other than the aforementioned receptors. In conclusion, this study suggests that glucosylceramide synthase and hydrocortisone may play important roles in modulating Gb3 levels in Fabry mouse aortic endothelial cells, and that endocytosis of recombinant α-galactosidase A involves a combination of multiple receptors depending on the properties of the enzyme.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Inherited Metabolic Disease
DOIs
StateAccepted/In press - Mar 10 2016

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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