锌转运蛋白 Zip14 影响小鼠肝脏再生过程中 c-Met 的磷酸化和肝细胞增殖。
The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice.
机构信息
Food Science and Human Nutrition Department, Center for Nutritional Sciences, College of Agricultural and Life Sciences, and Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.
出版信息
Gastroenterology. 2012 Jun;142(7):1536-46.e5. doi: 10.1053/j.gastro.2012.02.046. Epub 2012 Feb 25.
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.
背景与目的
细胞内的锌稳态通过锌转运体对锌内流、外排和向细胞内细胞器分布的严格调节来维持。Zrt-Irt 样蛋白（ZIP）转运体促进锌向细胞质内流入。炎性细胞因子可诱导 ZIP 家族成员 Zip14 的表达，而这些细胞因子也可启动肝再生。肝细胞增殖是肝再生所必需的。锌调节细胞增殖、组织生长和许多有丝分裂信号通路；我们研究了其在肝细胞中的作用。
方法
我们使用野生型和经部分肝切除术（切除 70%的肝脏）的 Zip14(-/-) 小鼠作为肝再生模型。我们还分析了过表达 Zip14 的 AML12 肝细胞。增殖通过增殖细胞核抗原、CD1 和 Ki67 标志物进行评估，并与锌含量测定相关联，与蛋白酪氨酸磷酸酶 1B（PTP1B）和细胞外信号调节激酶 1/2 信号通路相关联。
结果
Zip14 在肝再生过程中上调，肝内锌含量增加。肝内锌含量增加抑制磷酸酶 PTP1B 的活性，并增加 c-Met 的磷酸化，从而促进肝细胞增殖。过表达 Zip14 的 AML12 细胞锌含量和增殖增加；PTP1B 被抑制，c-Met 的磷酸化增加。在 Zip14(-/-) 小鼠中，部分肝切除术后发生的肝内锌水平升高和肝细胞增殖并未观察到。
结论
转运体 Zip14 在肝再生过程中以及在肝细胞增殖过程中介导肝脏摄取锌。这些发现表明，锌转运体活性通过螯合锌来调节肝组织生长。调节 ZIP14 活性的试剂可能被开发为治疗慢性肝病患者的肝再生的治疗方法。
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