title: Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins.
abstract: Silybin, the major flavonoid of Silybum marianum, is widely used to treat liver diseases such as hepatocellular carcinoma and cirrhosis-associated insulin resistance. Research so far has focused on its anti-oxidant properties. Here, we demonstrate that silybin and its derivative dehydrosilybin inhibit glucose uptake in several model systems. Both flavonoids dose-dependently reduce basal and insulin-dependent glucose uptake of 3T3-L1 adipocytes, with dehydrosilybin showing significantly stronger inhibition. However, insulin signaling was not impaired, and immunofluorescence and subcellular fractionation showed that insulin-induced translocation of GLUT4 to the plasma membrane is also unchanged. Likewise, hexokinase activity was not affected suggesting that silybin and dehydrosilybin interfere directly with glucose transport across the PM. Expression of GLUT4 in CHO cells counteracted the inhibition of glucose uptake by both flavonoids. Moreover, treatment of CHO cells with silybin and dehydrosilybin reduced cell viability which was partially rescued by GLUT4 expression. Kinetic analysis revealed that silybin and dehydrosilybin inhibit GLUT4-mediated glucose transport in a competitive manner with K(i)=60 and 116 µM, respectively. We conclude that silybin and dehydrosilybin inhibit cellular glucose uptake by directly interacting with GLUT transporters. Glucose starvation offers a novel explanation for the anti-cancer effects of silybin.
authors.affiliation: Molecular Cell Biology Laboratory, Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 345, D-69120 Heidelberg, Germany.
authors.forename: Tianzuo
authors.initials: T
authors.lastname: Zhan
authors.forename: Margarete
authors.initials: M
authors.lastname: Digel
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Küch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Joachim
authors.initials: J
authors.lastname: Füllekrug
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003847:Deoxyglucose / Q000378:metabolism; D057075:Enzyme Assays; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D011993:Recombinant Fusion Proteins; D012838:Silymarin; C505647:Tbc1d4 protein, mouse; C515097:dehydrosilybin; D000077385:Silybin; D003847:Deoxyglucose; D006593:Hexokinase; D051058:Oncogene Protein v-akt; D005947:Glucose