Metallothionein in mice reduces intestinal zinc loss during acute endotoxin inflammation, but not during starvation or dietary zinc restriction

Abstract

Normal metallothionein [(MT)+/+] and MT-null (MT-/-) mice were used to examine the influence of MT on Zn retention and the metabolic consequences of 2 d food deprivation, with and without inflammation induced by intraperitoneal injection of bacterial endotoxin lipopolysaccharide (LPS). LPS reduced fecal Zn concentration in MT+/+ mice from 5.9 ± 0.2 μmol/g on d 1 to 2.2 ± 0.2 μmol/g on d 2, but not in MT-/- mice, 5.9 ± 0.2 and 5.7 ± 0.5 μmol/g, respectively. MT+/+ mice fed an 8 mg Zn/kg diet and injected with LPS excreted 40% less Zn over 2 d than their MT-/- counterparts. Starvation for 2 d did not lower fecal Zn concentration in either genotype, although in MT+/+ mice, urinary Zn excretion was reduced from 12.7 ± 1.3 nmol on d 1 to 5.9 ± 1.8 nmol on d 2 and plasma Zn concentration was lowered to 9.8 ± 0.4 μmol/L. Zn was not reduced in urine or plasma of MT-/- mice, with respective values of 10.8 ± 2.0 nmol on d 1, 9.3 ± 2.9 nmol on d 2 and 13.0 ± 1.0 μmol/L. LPS injection resulted in much higher total liver Zn (677 ± 27 nmol) and MT (106 ± 2 nmol Cd bound/g) than starvation (Zn = 405 ± 21, MT = 9 ± 3) in MT+/+ mice after 2 d, but did not further reduce urinary Zn. LPS-injected MT-/- mice had no rise in liver Zn or fall in plasma and urine Zn. MT-/- mice fed a Zn-deficient (0.8 mg Zn/kg) diet lost 10% of body weight over 25 d compared with no loss in MT+/+ mice. Despite this, MT- /- mice excreted no more Zn via the gut than did MT+/+ mice. In summary, MT inhibits intestinal Zn loss when highly expressed. When uninduced, typically during Zn deficiency, MT appears to conserve Zn and body mass by reducing only urinary and other nonintestinal Zn losses.