The Zinc Transporter Zip14 Influences c-Met Phosphorylation and Hepatocyte Proliferation During Liver Regeneration in Mice

Abstract

BACKGROUND & AIMS Zinc homeostasis in cells is maintained through tight regulation of zinc influx, efflux, and distribution to intracellular organelles by zinc transporters. The Zrt-Irt-like protein (ZIP) transporters facilitate zinc influx to the cytosol. Expression of the ZIP family member Zip14 can be induced by inflammatory cytokines, which also initiate liver regeneration. Hepatocyte proliferation is required for liver regeneration. Zinc regulates cell proliferation, tissue growth, and many mitogenic signaling pathways; we investigated its role in hepatocytes. METHODS Wild-type and Zip14−/− mice that underwent partial hepatectomy (70% of liver removed) were used as models of liver regeneration. We also analyzed AML12 hepatocytes that overexpressed Zip14. Proliferation was assessed with proliferating cell nuclear antigen, CD1, and Ki67 markers and along with assays of zinc content was related to protein tyrosine phosphatase 1B (PTP1B) and extracellular signal–regulated kinase 1/2 signaling. RESULTS Zip14 was up-regulated and hepatic zinc content increased during liver regeneration. Increased hepatic zinc inhibited activity of the phosphatase PTP1B and increased phosphorylation of c-Met, which promoted hepatocyte proliferation. AML12 cells that overexpressed Zip14 increased in zinc content and proliferation; PTP1B was inhibited and phosphorylation of c-Met increased. The increases in hepatic levels of zinc and hepatocyte proliferation that occurred following partial hepatectomy were not observed in Zip14−/− mice. CONCLUSIONS The transporter Zip14 mediates hepatic uptake of zinc during liver regeneration and for hepatocyte proliferation. These findings indicate that zinc transporter activity regulates liver tissue growth by sequestering zinc. Reagents that regulate ZIP14 activity might be developed as therapeutics to promote liver regeneration in patients with chronic liver disease.

Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

“…Ϫ/Ϫ ) mice have been described previously (3,5,33 65 Zn was measured via ␥-scintillation spectrometry. For the antibiotic experiment, ultrapure (MiliQ, Billerica, MA) drinking water was supplemented with neomycin (0.5 mg/ml) and ampicillin (1 mg/ml) for 4 wk prior to tissue collection.…”

“…All other primer sequences were selected using the qPrimerDepot database, http://mouseprimerdepot.nci.nih.gov/, as described in Cui et al (17). TBP mRNA was the normalizer for relative expression, as described previously (3,5).…”

“…Western analysis was performed using polyclonal rabbit antibodies against ZIP14 developed and affinity purified (Life Technologies, Thermo Fisher Scientific) as described previously (3,5 ), MyD88, NF-B, phosphorylated NF-B (p65), PPAR␥, preadipocyte factor-1 (PREF-1/DLK-1), SOCS3, STAT3, and phosphorylated STAT3 (p-Y 705 ) antibodies were purchased from Cell Signaling Technology (Boston, MA). F4/80 and zinc ␣2-glycoprotein (ZAG) antibody were purchased from Santa Cruz Biotechnology (Dallas, TX).…”

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

“…Zinc is a known inhibitor of PTP1B through physical binding to the enzyme (32). We previously reported that overexpression of ZIP14 in AML12 hepatocytes suppressed PTP1B activity (33).…”

Clinical Significance of Joint Detection of Serum VEGF, SIL-2R and HGF in Patients with Primary Hepatocellular Carcinoma before and after Percutaneous Microwave Coagulation Therapy

“…However, increased HGF concentration may accelerate the metastasis and recurrence of liver cancer if micrometastasis is accompanied. The reason lies in HGF receptor c-Met has a high expression rate in the liver cell tissue of liver cancer (Aydemir et al, 2012), and a small amount of HGF can stimulate the growth of micrometastatic lesions.…”