A major feedback mechanism of cholesterol in transcription of cholesterol metabolism-related genes is mediated by sterol regulatory element-binding protein (SREBP). Involvement of glycosphingolipids (GSLs) in the SREBP pathway is unknown. Ill this study, we examined the effects of GSL depletion oil SIRE-mediated gene transcription using GSL-defective cells. We found that the content of mature SREBP, the transcriptional active form, is increased in the GSL-defective cells. Transcription of SREBP target genes and cholesterol synthesis are also induced in the GSL-defective cells. These results indicate that GSL deficiency Up-regulates the SREBP pathway, pointing Out the regulatory role of GSL in cholesterol homeostasis. (C) 2008 Elsevier Inc. All rights reserved.