Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation

J Clin Invest. 2000 Jun;105(11):1563-71. doi: 10.1172/JCI9711.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives
  • 1-Deoxynojirimycin / pharmacology
  • Animals
  • Dose-Response Relationship, Drug
  • Fabry Disease / metabolism*
  • Kidney / metabolism
  • Kidney / ultrastructure
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Propanolamines / pharmacology
  • Pyrrolidines / pharmacology
  • Trihexosylceramides / metabolism*


  • 3',4'-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-1-propanol
  • Propanolamines
  • Pyrrolidines
  • Trihexosylceramides
  • 1-Deoxynojirimycin
  • globotriaosylceramide
  • miglustat