title: Reduced glucosylceramide in the mouse model of Fabry disease: correction by successful enzyme replacement therapy.
abstract: Fabry disease is an X-linked lysosomal storage disease (LSD) caused by deficient activity of α-Galactosidase A (α-Gal A). As a result, glycosphingolipids, mainly globotriaosylceramide (Gb3), progressively accumulate in body fluids and tissues. Studies aiming at the identification of secondary lipid alterations in Fabry disease may be potentially useful for the monitorization of the response to enzyme replacement therapy (ERT) and development of future therapies. The focus of this study was to evaluate if α-Gal A deficiency has an effect on two key groups of molecules of sphingolipids metabolism: glucosylceramides (GlucCers) and ceramides (Cers). Studies performed in a mouse model of Fabry disease showed reduced level of GlucCer and normal level of Cer in plasma, liver, spleen, kidney and heart. Moreover, analysis of GlucCer isoforms in Fabry knockout mice showed that GlucCer isoforms are unequally reduced in different tissues of these animals. ERT had a specific effect on the liver's GlucCer levels of Fabry knockout mice, increasing hepatic GlucCer to the levels observed in wild type mice. In contrast to Fabry knockout mice, plasma of Fabry patients had normal GlucCer and Cer but an increased GlucCer/Cer ratio. This alteration showed a positive correlation with plasma globotriaosylsphingosine (lyso-Gb3) concentration. In conclusion, this work reveals novel secondary lipid imbalances caused by α-Gal A deficiency.
authors: Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre no. 823, 4150-180, Porto, Portugal; School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal. Electronic address: ruiquinta@ibmc.up.pt.
authors: Rui
authors: R
authors: Quinta
authors: Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre no. 823, 4150-180, Porto, Portugal. Electronic address: danielr@ibmc.up.pt.
authors: Daniel
authors: D
authors: Rodrigues
authors: Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre no. 823, 4150-180, Porto, Portugal. Electronic address: marisa.assuncao@ibmc.up.pt.
authors: Marisa
authors: M
authors: Assunção
authors: Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre no. 823, 4150-180, Porto, Portugal; SACS, University of Aveiro, Aveiro, Portugal. Electronic address: fmacedo@ibmc.up.pt.
authors: Maria Fatima
authors: MF
authors: Macedo
authors: School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal; Cardiology Department, Centro Hospitalar do Alto Ave, Rua dos Cutileiros, 4835-044 Guimarães, Portugal. Electronic address: olgazevedo@yahoo.com.br.
authors: Olga
authors: O
authors: Azevedo
authors: School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal. Electronic address: damiaojlcunha@gmail.com.
authors: Damião
authors: D
authors: Cunha
authors: Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal. Electronic address: pnoliveira@icbas.up.pt.
authors: Pedro
authors: P
authors: Oliveira
authors: Lysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre no. 823, 4150-180, Porto, Portugal. Electronic address: mcsamir@ibmc.up.pt.
authors: Maria Clara
authors: MC
authors: Sá Miranda
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005963:Glucosylceramides / Q000097:blood*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D005963:Glucosylceramides; D000519:alpha-Galactosidase
keywords: Cer; Ceramide; ERT; Enzyme replacement therapy; Fabry disease; Fabry mice; GSL; Gb3; GlucCer; Glucosylceramide; LSD; Lyso-Gb3; ceramide; globotriaosylceramide; globotriaosylsphingosine; glucosylceramide; glycosphingolipid; lysosomal storage disease