{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T22:09:24Z","timestamp":1755036564815},"reference-count":46,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2006,5,4]],"date-time":"2006-05-04T00:00:00Z","timestamp":1146700800000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2006,5]]},"abstract":"<jats:p>We have shown that the ABC transporter, multiple drug resistance protein\u20031 (MDR1, P\u2010glycoprotein) translocates glucosyl ceramide from the cytosolic to the luminal Golgi surface for neutral, but not acidic, glycosphingolipid (GSL) synthesis. Here we show that the MDR1 inhibitor, cyclosporin\u2003A (CsA) can deplete Gaucher lymphoid cell lines of accumulated glucosyl ceramide and Fabry cell lines of globotriaosyl ceramide (Gb<jats:sub>3<\/jats:sub>), by preventing <jats:italic>de novo<\/jats:italic> synthesis. In the Fabry mouse model, Gb<jats:sub>3<\/jats:sub> is increased in the heart, liver, spleen, brain and kidney. The lack of renal glomerular Gb<jats:sub>3<\/jats:sub> is retained, but the number of verotoxin\u20031 (VT1)\u2010staining renal tubules, and VT1 tubular targeting <jats:italic>in vivo<\/jats:italic>, is markedly increased in Fabry mice. Adult Fabry mice were treated with \u03b1\u2010galactosidase (enzyme\u2010replacement therapy, ERT) to eliminate serum Gb<jats:sub>3<\/jats:sub> and lower Gb<jats:sub>3<\/jats:sub> levels in some tissues. Serum Gb<jats:sub>3<\/jats:sub> was monitored using a VT1 ELISA during a post\u2010ERT recovery phase \u00b1 biweekly intra peritoneal CsA. After 9\u2003weeks, tissue Gb<jats:sub>3<\/jats:sub> content and localization were determined using VT1\/TLC overlay and histochemistry. Serum Gb<jats:sub>3<\/jats:sub> recovered to lower levels after CsA treatment. Gb<jats:sub>3<\/jats:sub> was undetected in wild\u2010type liver, and the levels of Gb<jats:sub>3<\/jats:sub> (but not gangliosides) in Fabry mouse liver were significantly depleted by CsA treatment. VT1 liver histochemistry showed Gb<jats:sub>3<\/jats:sub> accumulated in Kupffer cells, endothelial cell subsets within the central and portal vein and within the portal triad. Hepatic venule endothelial and Kupffer cell VT1 staining was considerably reduced by <jats:italic>in vivo<\/jats:italic> CsA treatment. We conclude that MDR1 inhibition warrants consideration as a novel adjunct treatment for neutral GSL storage diseases.<\/jats:p>","DOI":"10.1111\/j.1742-4658.2006.05223.x","type":"journal-article","created":{"date-parts":[[2006,5,4]],"date-time":"2006-05-04T09:38:01Z","timestamp":1146735481000},"page":"2064-2075","source":"Crossref","is-referenced-by-count":17,"title":["Treatment of neutral glycosphingolipid lysosomal storage diseases via inhibition of the ABC drug transporter, MDR1"],"prefix":"10.1111","volume":"273","author":[{"given":"Michael","family":"Mattocks","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Bagovich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"De 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