Kidney lipids in galactosylceramide synthase-deficient mice: absence of galactosylsulfatide and compensatory increase in more polar sulfoglycolipids

UDP-galactose:ceramide galactosyltransferase (CGT) catalyzes the final step in the synthesis of glactosylceramide (GalCer). It has previously been sho wn that CGT-deficient mice do not synthesize GalCer and its sulfated deriva tive GalCer Is-sulfate (galactosylsulfatide, SM4s) but form myelin containi ng glucosylceramide (GlcCer) and sphingomyelin with 2-hydroxy fatty acids, Because relatively high concentrations of GalCer and SM4s are present also in mammalian kidney, we analyzed the composition of lipids in the kidney of Cgt(-/-) and, as a control, Cgt(-/-) and wildtype mice. The homozygous mut ant mice lacked GalCer, galabiaosylceramide (Ga(2)Cer), and SM4s, Yet, they did not show any major morphological or functional defects in the kidney, A slight increase in GlcCer containing 4-hydroxysphinganine was evident amo ng neutral glycolipids. Intriguingly, more polar sulfoglycolipids, that is, lactosylceramide H-3-sulfate (SM3) and gangliotetraosylceramide II3,IV3-bi s-sulfate (SB1a), were expressed at 2 to 3 times the normal levels in Cgt(- /-) mice, indicating upregulation of biosynthesis of SB1a from GlcCer via S M3, Given that SM4s is a major polar glycolipid constituting renal tubular membrane, the increase in SM3 and SB1a in the mice deficient in CGT and thu s SM4s appears to be a compensatory process, which could partly restore kid ney function in the knockout mice.