Metallothionein and liver cell regeneration

Abstract

Hepatocytes in adults are in a nonproliferative state but they have high capacity to regenerate within few hours after an injury. After partial hepatectomy or chemical injury, hepatocytes undergo a synchronized multistep process consisting of priming/initiation, proliferation, and termination. These distinct steps are essential for restoring the structure and functions of liver. The mechanisms involved in each of these steps of regeneration are well documented from various laboratories and are described in several reviews. We briefly describe these steps and the involvement of various cytokines and growth factors for cell regeneration in this short review. Liver cell regeneration may also involve stem cell proliferation. The regenerating cells require large amounts of zinc within a short time, and this requirement is met by induction of a zinc and copper binding protein, metallothionein (MT), during the priming step, soon after an injury. There are several reports on the transfer of zinc from MT to various metalloenzymes and transcription factors. Genetically modified mouse models have been used to study the involvement of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in cell regeneration. The use of an MT-knockout mouse has enabled us to investigate the specific role of MT in liver regeneration after partial hepatectomy, chemical injury, and fibrosis. Several studies have suggested a defective liver regeneration after an injury in MT-knockout mice. There is cumulative evidence that indicates an essential role for MT in liver cell regeneration.