Endotoxin-induced inflammation does not cause hepatic zinc accumulation in mice lacking metallothionein gene expression

Abstract

The action of endotoxin lipopolysaccharide (LPS) on hepatic Zn uptake was examined in mice lacking expression of metallothionein (MT)-1 and MT-II genes. Hepatic Zn concentrations, which in normal control mice increased by a mean 29% (MT elevated 20-fold) 16 h post-LPS exposure, did not increase in MT-null mice. Plasma Zn fell by 68% in controls and 32% in MT-null mice. The time course of LPS action in normal mice was characterized by a rapid reduction (-74% at 4 h, -81% at 8 h) and partial recovery (-39% at 24 h) in plasma Zn, with a progressive increase over 24 h in hepatic concentrations of MT (by 36-fold) and Zn (by 40%). In contrast, the MT-null mice had a linear decrease in plasma Zn (-15% at 8 h, -41% at 24 h) and early loss of Zn from the liver. The Zn changes seen in MT-null mice were largely attributable to LPS-associated anorexia. Food deprivation (20 h) alone caused respective 14% and 30% decreases in hepatic and plasma Zn concentrations and a 27% reduction in total liver Zn reserves, whereas fasted normal mice conserved Zn with a 4-fold increase in hepatic MT. This study confirms that MT synthesis is essential for endotoxin-induced liver Zn accumulation.

Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury

“…1C) (28,47). Importantly, the lack of zinc translocation in MT-null mice was associated with a resistant phenotype to hyperoxia (Figs.…”

“…In the presence of excess plasma zinc secondary to zinc infusion or exposure to dexamethasone or IL-6, metallothionein-mediated zinc transport into the liver occurs as a mechanism for maintaining zinc homeostasis (6). Hepatic zinc accumulation is particularly vital in inflammation and infection, supporting zinc-dependent acute phase reactions and host defense mechanisms, and MT is required for zinc accumulation in the livers of endotoxin-treated mice (47). Insight into the molecular mechanisms in the setting of sepsis (5) and liverdirected aseptic injury (e.g., turpentine) are evolving, and important roles for metallothionein and zinc transporters are becoming more apparent (32,34).…”

Dietary Zinc Supplementation Ameliorates LPS-Induced Teratogenicity in Mice

“…Because only 0.1% of total body Zn is in the plasma, a sudden increase in Zn uptake by the liver can greatly depress plasma Zn concentration (26,28). Such a scenario in early pregnancy is highly unfavorable because the maternal plasma compartment acts as the conduit for fetal Zn supply.…”

“…Previous studies employing various teratogens(including urethane, ␣-hederin, 6-mercaptopurine, TNF-␣, and valproic acid) suggested that MT and its associated changes in maternal-fetal Zn distribution were the key mediators of teratogenicity (19 -24). We and others have shown that alcohol (25) and LPS (26,27) are all potent inducers of MT in the liver resulting in sequestration of plasma Zn in the liver, with a consequent decrease in plasma Zn concentration.…”

Protective Effect of Zinc against Lipopolysaccharide/D-Galactosamine-Induced Lethality.

“…[8][9][10] Philcox et al reported that lipopolysaccharide (LPS) did not induce hepatic zinc uptake in mice lacking expression of MT-I and MT-II genes. 11) MT may have a role in maintaining hepatic and blood glucose levels during endotoxemia. 12) We previously reported that MT-I and II-deficient (MT-null) mice are highly sensitive to the lethal effects of LPS/D-galactosamine (GalN).…”