Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation.
We used a potent inhibitor of glucosylceramide synthase to test whether substrate deprivation could lower globotriaosylceramide levels in alpha-galactosidase A (alpha-gal A) knockout mice, a model of Fabry disease. C57BL/6 mice treated twice daily for 3 days with D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidi no-propanol (D-t-EtDO-P4) showed a concentration-dependent decrement in glucosylceramide levels in kidney, liver, and spleen. A single intraperitoneal injection of D-t-EtDO-P4 resulted in a 55% reduction in renal glucosylceramide, consistent with rapid renal glucosylceramide metabolism. A concentration-dependent decrement in renal and hepatic globotriaosylceramide levels was observed in alpha-Gal A(-) males treated for 4 weeks with D-t-EtDO-P4. When 8-week-old alpha-Gal A(-) males were treated for 8 weeks with 10 mg/kg twice daily, renal globotriaosylceramide fell to below starting levels, consistent with an alpha-galactosidase A-independent salvage pathway for globotriaosylceramide degradation. Complications observed with another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, including weight loss and acellularity of lymphatic organs, were not observed with D-t-EtDO-P4. These data suggest that Fabry disease may be amenable to substrate deprivation therapy.
Abe
A
A
Nephrology Division, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Gregory
S
S
Lee
L
L
Killen
P D
PD
Brady
R O
RO
Kulkarni
A
A
Shayman
J A
JA
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000795:Fabry Disease / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011412:Propanolamines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D014281:Trihexosylceramides / Q000378:metabolism*
C404730:3',4'-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-1-propanol; D011412:Propanolamines; D011759:Pyrrolidines; D014281:Trihexosylceramides; D017485:1-Deoxynojirimycin; C018549:globotriaosylceramide; C059896:miglustat