Metallothionein (MT) -I and MT-II Expression Are Induced and Cause Zinc Sequestration in the Liver after Brain Injury

Abstract

Experiments with transgenic over-expressing, and null mutant mice have determined that metallothionein-I and -II (MT-I/II) are protective after brain injury. MT-I/II is primarily a zinc-binding protein and it is not known how it provides neuroprotection to the injured brain or where MT-I/II acts to have its effects. MT-I/II is often expressed in the liver under stressful conditions but to date, measurement of MT-I/II expression after brain injury has focused primarily on the injured brain itself. In the present study we measured MT-I/II expression in the liver of mice after cryolesion brain injury by quantitative reverse-transcriptase PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) with the UC1MT antibody. Displacement curves constructed using MT-I/II knockout (MT-I/II−/−) mouse tissues were used to validate the ELISA. Hepatic MT-I and MT-II mRNA levels were significantly increased within 24 hours of brain injury but hepatic MT-I/II protein levels were not significantly increased until 3 days post injury (DPI) and were maximal at the end of the experimental period, 7 DPI. Hepatic zinc content was measured by atomic absorption spectroscopy and was found to decrease at 1 and 3 DPI but returned to normal by 7DPI. Zinc in the livers of MT-I/II−/− mice did not show a return to normal at 7 DPI which suggests that after brain injury, MT-I/II is responsible for sequestering elevated levels of zinc to the liver. Conclusion: MT-I/II is up-regulated in the liver after brain injury and modulates the amount of zinc that is sequestered to the liver.

Pathology of inherited manganese transporter deficiency

“…Cell culture studies indicate that Mn exposure results in increased ROS and hydrogen peroxide levels. 16 Consistent with these findings, our patient's hepatic Zn was increased 3-fold; however, it was not increased in the brain. 14,15 Additionally, brain injury can induce MT expression in the liver.…”

“…14,15 Additionally, brain injury can induce MT expression in the liver. 16 Consistent with these findings, our patient's hepatic Zn was increased 3-fold; however, it was not increased in the brain. In the absence of a specific histological method to detect Mn, we performed rhodanine staining, frequently used to demonstrate tissue accumulation of Mn and Cu; rhodamine-positive staining was present in the patient's brain and liver.…”

Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity

“…) and metallothionein 1 (Mt1) and 2 (Mt2) (Pankhurst et al . ), and GABA‐related genes, including GABA A receptor α1 (GABRA1), GABA A receptor α2 (GABRA2) (Fujimura et al . ), glutamate decarboxylase 65 (GAD65), glutamate decarboxylase 67 (GAD67), and GABA transporter (GAT) (Takano et al .…”

“…Primers were obtained from Eurofins, MWG Operon (Huntsville, AL, USA). These primers are copper-related genes, including Atp7a, Atp7b, Ctr1 (Bauerly et al 2005), Cp (Lestaevel et al 2009) and metallothionein 1 (Mt1) and 2 (Mt2) (Pankhurst et al 2012), and GABA-related genes, including GABA A receptor a1 (GABRA1), GABA A receptor a2 (GABRA2) (Fujimura et al 2005), glutamate decarboxylase 65 (GAD65), glutamate decarboxylase 67 (GAD67), and GABA transporter (GAT) (Takano et al 2014). The expression level of each gene was normalized to that of cyclophilin and analyzed by the comparative Ct method (2 ÀDCt ) (Schmittgen and Livak 2008).…”

Metallothionein Expression in Dogs With Chronic Hepatitis and Its Correlation With Hepatic Fibrosis, Inflammation, and Ki-67 Expression

“…24 The MT-I and MT-II isoforms are often considered a single species (referred to here as MT) due to their high homology and the inability of primary antibodies to differentiate between the 2 forms. 16 Both forms are ubiquitous in mammalian tissues and increase in the liver after heavy metal exposure, which is thought to be protective against heavy metal-induced liver injury. 2 It has been shown that COMMD1-deficient dogs, which progressively develop copper-induced CH, display a significant increase of MT expression at 12 months of age, coinciding with the massive accumulation of copper despite the absence of liver disease.…”