ZINC, VANADATE AND SELENATE INHIBIT THE TRI-IODOTHYRONINE-INDUCED EXPRESSION OF FATTY-ACID SYNTHASE AND MALIC ENZYME IN CHICK-EMBRYO HEPATOCYTES IN CULTURE

Insulin regulates the expression of genes involved in a variety of met abolic processes. In chick-embryo hepatocytes in culture, insulin ampl ifies the tri-iodothyronine (T-3)-induced enzyme activity, and the lev el and rate of transcription of mRNA for both fatty acid synthase (FAS ) and malic enzyme (ME). Insulin alone, however, has little or no effe ct on the expression of these genes. In chick-embryo hepatocytes, the mechanism by which insulin regulates the expression of these or other genes is not known. Several recent studies have compared the effects o f zinc, vanadate and selenate on insulin-sensitive processes in an att empt to probe the mechanism of insulin action. Because zinc, vanadate and selenate mimic the effects of insulin on several processes, they h ave been termed insulin-mimetics. We have studied the effect of zinc, vanadate and selenate on the T-3-induced expression of both FAS and ME . Like insulin, these agents had little or no effect on the basal acti vities for FAS and ME in chick-embryo hepatocytes in culture for 48 h. Unlike insulin, however, zinc, vanadate and selenate inhibited the T- 3-induced activities and mRNA levels of both FAS and ME. Maximal inhib ition was achieved at concentrations of 50 mu M zinc or vanadate, or 2 0 mu M selenate. Zinc and vanadate also inhibited the T-3-induced tran scription of the FAS and ME genes. Although the mechanism of this inhi bition is unknown, our results indicate that it is not mediated throug h inhibition of binding of T-3 to its nuclear receptor nor through a g eneral toxic effect. Thus zinc, vanadate and selenate are not insulin- mimetics under all conditions, and their effects an other insulin-sens itive processes may be fortuitous and unrelated to actions or componen ts of the insulin signalling pathway.