title: Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation.
abstract: 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.
authors.affiliation: Nephrology Division, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: A
authors.initials: A
authors.lastname: Abe
authors.forename: S
authors.initials: S
authors.lastname: Gregory
authors.forename: L
authors.initials: L
authors.lastname: Lee
authors.forename: P D
authors.initials: PD
authors.lastname: Killen
authors.forename: R O
authors.initials: RO
authors.lastname: Brady
authors.forename: A
authors.initials: A
authors.lastname: Kulkarni
authors.forename: J A
authors.initials: JA
authors.lastname: Shayman
mesh_terms: 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*
chemical_list: C404730:3',4'-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-1-propanol; D011412:Propanolamines; D011759:Pyrrolidines; D014281:Trihexosylceramides; D017485:1-Deoxynojirimycin; C018549:globotriaosylceramide; C059896:miglustat