Coordinate regulation of zinc metabolism and metallothionein gene expression in rats

Abstract

Regulation of zinc metabolism by dibutyryl cAMP, glucagon, and epinephrine was examined in rats fed adequate amounts of zinc. Dibutyryl cAMP, epinephrine, and glucagon each produced an increase in liver metallothionein levels by 10 h after they were first administered. The increase in liver metallothionein was inversely related to the serum zinc concentration. Treatment with dexamethasone, a glucocorticoid, accentuated these effects to some extent. Both metallothionein I and II were induced by dibutyryl cAMP and glucagon. Levels of metallothionein mRNA in total liver RNA extracts were measured by dot blot hybridization using a synthetic 21-base oligonucleotide complimentary to the 5' region of both the metallothionein I and II genes. Individual administration of dibutyryl cAMP, glucagon, and epinephrine increased the number of metallothionein mRNA molecules per cell by up to fourfold. The data suggest that glucagon and epinephrine are primary regulators of metallothionein gene expression acting at least in part via cAMP. In adrenalectomized rats, glucagon, dibutyryl cAMP, and epinephrine had a less potent effect in terms of metallothionein induction and depression of serum zinc concentrations. These effects were largely restored when dexamethasone was also given. Collectively these data suggest that changes in zinc metabolism associated with acute stress involve coordinate regulation mediated by many factors, including glucocorticoids and cAMP.

TSH induces metallothionein 1 in thyrocytes via Gq/11- and PKC-dependent signaling

“…A well-established mechanism of TSHR-induced gene regulation comprises G s -and cAMP-dependent activation of PKA and subsequent cAMP-responsive element-binding protein (CREB) binding to cAMP-responsive promoter elements. Of note, cAMP-dependent gene regulation has also been described for MTs in nonthyroid cell systems (Cousins et al 1986). By comparing the effect of the unspecific adenylyl cyclase activator FSK and that of TSH in FTC-133 wtTSHR cells on MT1X regulation, we found that FSK induced MT1X in a strictly PKA-dependent mechanism, whereas TSH-promoted induction of MT1X expression did not require any contribution of PKA.…”

“…Previous studies in different cells using stimuli other than TSH have reported that elevations of cAMP might mediate an induction of MT expression (Cousins et al 1986). A contribution of cAMP signaling to the TSH-promoted regulation of MT1X would be plausible since a G s -dependent increase in cAMP levels is the best established cellular response after TSH stimulation.…”

Functional Analyses of the Human Metallothionein-IG Gene

“…Under conditions for TATA box competition and optimal MT-IG transcription (45 g), significant competition effects were not observed (data not shown). This suggests that an extreme excess of MRE-binding factors is present in the extracts, which could be expected from the high level of MT expression in rat liver (24,25). Alternatively, we have observed that MRE oligonucleotides form more nonspecific than specific complexes in rat liver extracts using mobility shift assays (data not shown).…”

Effect of Insulin Treatment or Zinc Supplementation on Vitamin A Status in Streptozotocin-Induced Diabetic Rats.

“…The accumulation of zinc in the diabetic liver has been suggested to be caused by increased levels of metallothionein, a zinc-binding cytoplasmic protein [17,27]. The hormones such as glucagon, glucocorticoid, and epinephrine are known to be stimulators of hepatic synthesis of this protein [29]. It is thought that insulin deficiency induces synthesis of these hormones and that this effect leads to an increase in hepatic metallothionein and zinc levels in the liver [27].…”