Trace metal, acute phase and metabolic response to endotoxin in metallothionein-null mice

Abstract

Accumulation of hepatic zinc via metallothionein (MT) induction during infection/inflammation is postulated to benefit a range of metabolic processes. The metabolic consequences of two doses of endotoxin (LPS) (1 and 5 mg/kg, intraperitoneally) were examined in normal (MT+/+) and MT-null (MT-/-) mice (all results means =/- S.E.M., n=6). At 16 h after 1 mg/kg LPS, hypozincaemia was pronounced in the MT+/+ mice (4.4+/-0.2 microM), concomitant with a 36% increase in hepatic Zn and a > 10-fold increase in hepatic MT. Plasma Zn (16.6+/-0.7 microM) and total hepatic Zn were unchanged in MT -/- mice, confirming the importance of MT in altering plasma and hepatic Zn during inflammation. Plasma iron was lower in LPS-treated MT-/- mice, whereas plasma copper increased to a similar extent in both groups of mice. Plasma fibrinogen more than doubled, and was similar in both groups of mice, which questions the importance of MT in acute-phase protein synthesis. Blood and liver glucose concentrations were not significantly different between groups before or after LPS, whereas blood and liver lactate concentrations were significantly lower (31% and 24% respectively) in MT-/- mice after LPS. At 16 h after 5 mg/kg LPS, plasma Zn was decreased even further in MT+/+ mice (2.6+/-0.3 microM), but remained unchanged in MT-/- mice at concentrations significantly above those in 16-h fasted MT-/- mice (15.8+/-0.5 versus 11.3+/-0.3 microM). Total liver Zn was 17% lower than fasting values in MT-/- mice, in contrast with 32% higher in MT+/+ mice. Synthesis of MT (in MT+/+ mice) and fibrinogen in all mice was not further enhanced by the higher LPS dose. Blood glucose was significantly decreased by 18% in MT+/+ mice and by 38% in MT-/- mice after 5 mg/kg LPS. There was a marked 44% decrease in liver glucose in MT-/- mice; that in MT+/+ mice was unchanged from fasting levels, implying a deficit in hepatic gluconeogenesis in LPS-treated MT-/- mice. In the absence of any indication of major hepatotoxicity, the results of this study indicate that energy production, and not acute-phase protein synthesis, may be most influenced by Zn supply during endotoxaemia, suggesting that MT has a role in maintaining hepatic and blood glucose in this metabolic setting.

Monitoring metal ion flux in reactions of metallothionein and drug‐modified metallothionein by electrospray mass spectrometry

“…The high abundance of Zn,-MT in Figure IB is consistent with the stability of this species reported by others (Vallee, 1995). It should be noted that a role has recently been proposed for MT in maintaining glucose levels in blood and liver (Rofe et al, 1996). Finally, the idea that thionein can deactivate its own transcription by extracting zinc ions from proteins that bind DNA was tested here using another DNA binding protein, the bacteriophage T4 gene 32 protein core domain.…”

“…1995;Philcox et al, 1995;Rofe et al, 1996). These types of stresses, while absent in benign laboratory conditions, are ubiquitous in the natural environment, and might thus provide the selective pressure behind the highly conserved ability to express MT (Steffens, 1990;Lazo et al, 1995;Vallee, 1995).…”

Nutrient-gene interactions: a single nutrient and hundreds of target genes

“…Evidence for a disturbed hepatic glucose metabolism comes from studies in zinc-deficient rats and in metallothionein-deficient mice ( Table 1). The basal hepatic glucose production in Zn-depleted rats for example was shown to be reduced (Faure et al, 1991) and in addition, MT-null mice with a low Zn concentration in liver also showed a reduced hepatic gluconeogenesis upon stimulation (Rofe et al, 1996). Moreover, a reduced rate of glycolysis was shown in isolated hepatocytes from MT y/y mice in comparison to cells obtained from control animals (Rofe et al, 1996(Rofe et al, , 2000.…”

“…The basal hepatic glucose production in Zn-depleted rats for example was shown to be reduced (Faure et al, 1991) and in addition, MT-null mice with a low Zn concentration in liver also showed a reduced hepatic gluconeogenesis upon stimulation (Rofe et al, 1996). Moreover, a reduced rate of glycolysis was shown in isolated hepatocytes from MT y/y mice in comparison to cells obtained from control animals (Rofe et al, 1996(Rofe et al, , 2000. Our findings based on hepatic transcriptome analysis suggest that Zn deficiency alters glucose utilization and glucose release in hepatocytes through a quite complex regulatory network including regulation at the transcriptome and protein levels, by protein-protein interactions and by allosteric and kinetic effects.…”

Preservation of Intestinal Structural Integrity by Zinc Is Independent of Metallothionein in Alcohol-Intoxicated Mice

“…In response to inflammatory stimuli such as endotoxins, "acute phase" proteins such as MT are induced, however, the effects of many of these endogenous agents following alcohol exposure remain unclear. 19,20 A study conducted by Takano et al 21 found that MT acted as a cytoprotectant against gastroduodenal mucosal injury caused by ethanol in mice. In that study, MT knockout (MT-KO) mice, in which the MT-I and MT-II genes were interrupted, were treated orally with ethanol and gastric and duodenal lesions were compared with wild-type mice.…”