Changes in hepatic gene expression in response to hepatoprotective levels of zinc

Abstract

Background Zinc (Zn) administration at non-toxic doses protects against the hepatotoxicity produced by many agents, but the underlying mechanisms remain elusive. Aim To examine the basis of Zn-induced generalised hepato-protective effects. Methods Rats and mice were given Zn at known hepato-protective levels (100 μmol ZnCl2/kg/day, s.c., for 4 days) and molecular responses were assessed. Results Zn treatment produced changes in 5% of the genes on custom-designed mouse liver array and Rat Toxicology-II array. Changes in gene expression were further confirmed and extended by real-time reverse transcriptase-polymerase chain reaction. Zn treatment dramatically increased the expression of the metallothionein (Mt), and modestly increased the expression of acute-phase protein genes (ceruloplasmin, Stat3, egr1, Cxc chemokines and heat-shock proteins). For genes encoding for antioxidant enzymes, some were increased (Nrf2 and Nqo1), while others remained unaltered (Cu, Zn SOD and glutathione S-transferases). Expressions of cytokine and pro-inflammatory genes were not affected, while genes related to cell proliferation (cyclin D1) were modestly upregulated. Some metabolic enzyme genes, including cytochrome P450s and UDP-glucuronosyltransferase, were modestly suppressed, perhaps to switch cellular metabolic energy to acute-phase responses. Liver Zn content was increased between 1.6- and 2.1-fold, while hepatic MT protein was increased between 50 and 200-fold. Mice typically showed greater responses than rats. Conclusion Such gene expression changes, particularly the dramatic induction of MT and Nrf2 antioxidant pathway, occur in the absence of overt liver injury, and are probably important in the hepatoprotective effects of Zn against toxic insults.

Association of serum zinc levels with liver function and survival in patients awaiting liver transplantation

“…Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response, but also mediates fibrosis progression through regulation of zinc-dependent endoproteinases highly expressed in hepatic stellate and Kupffer cells [32]. In vitro and in vivo studies addressing the role of zinc supplementation at non-toxic doses further demonstrated that zinc protects against hepatotoxicity, which is likely mediated by its regulatory role of acute-phase protein genes [2]. Thus, it is tempting to speculate that the altered innate immune response caused by zinc deficiency [5] might also be responsible for the altered disease progression of PSC patients observed in this study.…”

“…In chronic liver dysfunction, particularly in cases of ALD and viral liver disease, serum zinc levels are reduced compared to healthy control populations [7,8]. A microarray analysis profiling genetic patterns associated with zinc supplementation indicated that zinc has a highly hepatoprotective function when administered at non-toxic doses [2].…”

“…Zinc is an abundant trace element with important regulatory, catalytic and defensive functions [1] and plays a major role in the regulation of hepatic gene expression [2]. Zinc's role in liver dysfunction has been primarily investigated in alcoholic liver disease (ALD) [3], in which the importance of the liver in regulating zinc storage and homeostasis has been demonstrated [4].…”

Chlorogenic acid prevents acetaminophen-induced liver injury: The involvement of CYP450 metabolic enzymes and some antioxidant signals

“…We found that AP decreased Fmo5 mRNA expression, but CGA failed to increase it. MT is a family of cysteine-rich, low-molecular-weight proteins, and it has been reported to protect against oxidative stress injury induced by exogenous agents (Bauman et al, 1991;Liu et al, 2009). In addition, there is a report that MT-null mice were more susceptible than wild mice to AP-induced hepatotoxicity, whereas zinc pretreatment, a method of inducing MT expression, protected against AP-induced hepatotoxicity (Liu et al, 1999).…”

Rapid changes in heat-shock cognate 70 levels, heat-shock cognate phosphorylation state, heat-shock transcription factor, and metal transcription factor activity levels in response to heavy metal exposure during sea urchin embryonic development

“…In the nuclei of P. lividus embryos, HSF binds HSE under physiological growth conditions (18-20°C), and this binding activity increases upon heat shock (31°C) (Sconzo et al 1997). Furthermore, metal treatment results in synthesis of HSPs and the induction of metallothionein (MT) genes (Forti et al 2010;Liu et al 2009;Natoli et al 2009). This induction is mediated by the cis-acting DNA element, the metal-responsive element (MRE).…”