TY - JOUR
T1 - Distinctive accumulation of globotriaosylceramide and globotriaosylsphingosine in a mouse model of classic Fabry disease
AU - Taguchi, Atsumi
AU - Ishii, Satoshi
AU - Mikame, Mariko
AU - Maruyama, Hiroki
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2023/3
Y1 - 2023/3
N2 - Fabry disease (FD) is an inherited disease caused by deficient α-galactosidase A activity that is characterized by the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Although plasma lyso-Gb3 is a sensitive biomarker of FD, the correlation between its concentration and clinical symptoms remains unclear. To clarify the influence of plasma Gb3 and lyso-Gb3 in a symptomatic GlatmTg(CAG-A4GALT) FD mouse model, the total contents of Gb3, lyso-Gb3 and their analogs in various organs and plasma were determined in mice with early- (5-week-old) and late-stage (20-week-old) renal dysfunction. A marked increase in total Gb3 content in the heart, kidneys, spleen, liver, small intestine, lungs, brain, and plasma was observed in the 20-week-old mice compared to that in 5-week-old mice. In contrast, the increase in lyso-Gb3 was relatively small, and the total content in the lungs and plasma was unchanged. Lyso-Gb3 analogs {lyso-Gb3(−2) and lyso-Gb3(+18)} and Gb3 analogs {Gb3(−2) and Gb3(+18)} were observed in all organs and plasma at both ages, and the percentages of the analogs were unique to specific organs. The pattern of 37 Gb3 analogs/isoforms of liver Gb3 corresponded well with that of plasma Gb3. Although the analog pattern of plasma lyso-Gb3 did not resemble that of any organ lyso-Gb3, the relative content {lyso-Gb3: lyso-Gb3(−2)} in the sum of all organs corresponded well to that of the plasma at both ages. These data indicate that liver Gb3 may contribute to the plasma Gb3 level, while plasma lyso-Gb3 may be released from all organs, and the capacity of the plasma lyso-Gb3 pool may reach a maximum at an early stage of renal dysfunction.
AB - Fabry disease (FD) is an inherited disease caused by deficient α-galactosidase A activity that is characterized by the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Although plasma lyso-Gb3 is a sensitive biomarker of FD, the correlation between its concentration and clinical symptoms remains unclear. To clarify the influence of plasma Gb3 and lyso-Gb3 in a symptomatic GlatmTg(CAG-A4GALT) FD mouse model, the total contents of Gb3, lyso-Gb3 and their analogs in various organs and plasma were determined in mice with early- (5-week-old) and late-stage (20-week-old) renal dysfunction. A marked increase in total Gb3 content in the heart, kidneys, spleen, liver, small intestine, lungs, brain, and plasma was observed in the 20-week-old mice compared to that in 5-week-old mice. In contrast, the increase in lyso-Gb3 was relatively small, and the total content in the lungs and plasma was unchanged. Lyso-Gb3 analogs {lyso-Gb3(−2) and lyso-Gb3(+18)} and Gb3 analogs {Gb3(−2) and Gb3(+18)} were observed in all organs and plasma at both ages, and the percentages of the analogs were unique to specific organs. The pattern of 37 Gb3 analogs/isoforms of liver Gb3 corresponded well with that of plasma Gb3. Although the analog pattern of plasma lyso-Gb3 did not resemble that of any organ lyso-Gb3, the relative content {lyso-Gb3: lyso-Gb3(−2)} in the sum of all organs corresponded well to that of the plasma at both ages. These data indicate that liver Gb3 may contribute to the plasma Gb3 level, while plasma lyso-Gb3 may be released from all organs, and the capacity of the plasma lyso-Gb3 pool may reach a maximum at an early stage of renal dysfunction.
KW - Analog
KW - Fabry disease
KW - GlaTg(CAG-A4GALT) Fabry mouse model
KW - Globotriaosylceramide
KW - Globotriaosylsphingosine
UR - http://www.scopus.com/inward/record.url?scp=85145392940&partnerID=8YFLogxK
U2 - 10.1016/j.ymgmr.2022.100952
DO - 10.1016/j.ymgmr.2022.100952
M3 - 学術論文
C2 - 36624895
AN - SCOPUS:85145392940
SN - 2214-4269
VL - 34
JO - Molecular Genetics and Metabolism Reports
JF - Molecular Genetics and Metabolism Reports
M1 - 100952
ER -