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Metallothionein (MT) is a cysteine-rich protein that binds to and is inducible by heavy metals such as cadmium and zinc. However, the precise mechanism of MT induction by other metals remains unclear. In the present study, we investigated the mechanism of MT induction by manganese, focusing on the involvement of cytokine production. Administration of MnCl 2 to mice resulted in the induction of MT dose-dependently in the liver with little accumulation of manganese. Speciation analysis of metals in the liver cytosol showed that the major metal bound to the induced MT was zinc. Administration of MnCl 2 caused an increase in mRNA levels of interleukin-6 (IL-6) in the liver as well as an increase in serum levels of IL-6 but not those of other inflammatory cytokines. Subsequently, serum levels of serum amyloid A (SAA), an acute-phase protein induced by IL-6, increased with a peak at 24 h. However, no increase in serum alanine aminotransferase activity was observed, suggesting that manganese enhanced the production of IL-6 and SAA without causing liver injury. In response to IL-6, the expression of a zinc transporter, ZIP14, was enhanced in the liver, possibly contributing to the synthesis of hepatic zinc-MT. In IL-6-null mice, the induction of hepatic MT by treatment with MnCl 2 was completely suppressed to the control level. These results suggest that manganese is a unique metal that induces the synthesis of hepatic MT completely depending on the production of IL-6 without accompanying liver injury.Metallothionein (MT) is a cysteine-rich low-molecularweight protein with a high affinity for heavy metals. Physiological roles of MT encompass a broad spectrum, including detoxification of heavy metals, scavenging of free radicals, regulation of cell growth, and maintenance of homeostasis of trace metals such as zinc and copper (Suzuki et al., 1993). The most prominent characteristic of MT is its inducibility not only by metals but also by various factors such as hormones, cytokines, organic chemicals, starvation, and physical stress (Kä gi, 1993). It is generally perceived that the expression of the MT gene in response to a metal load is regulated by metal-responsive transcription factor 1 (MTF-1) that binds to the metal-response elements of the promoter region of MT genes (Heuchel et al., 1994). The mechanisms underlying the activation of the MT gene through the interaction of MTF-1 and metal-response elements have been investigated extensively (Andrews, 2001;Otsuka, 2004), but the precise mechanism of MT induction by nonzinc metals, including cadmium has been poorly understood (Daniels et al., 2002;Wang et al., 2004).In addition to potent MT-inducing metals such as zinc, cadmium, copper, mercury, silver, and bismuth, other metals such as chromium, iron, cobalt, nickel, arsenic, and manganese can also induce MT but to the lesser levels (Fleet et al., 1990;Albores et al., 1992). These weak MT-inducing metals

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Bezafibrate improved hepatic steatosis and potently prevented inflammation, oxidative stress, HSC activation, and fibrogenesis in the liver. Moreover, this study was the first to demonstrate that bezafibrate directly inhibits hepatic fibrogenic response induced by TGF-beta1 in vitro. Hence bezafibrate may be a new therapeutic strategy against NASH and hepatic fibrosis.

Metallothionein (MT) is a small sulfydryl-rich protein that binds to and is inducible by heavy metals such as mercury, cadmium, zinc, and copper. However, little is known about the induction of MT by trivalent metals except for bismuth. In this study, we examined the induction of MT synthesis by cerium, a trivalent lanthanoid metal. Administration of cerium chloride (CeCl3) to mice resulted in accumulation of cerium and induction of MT in the liver in a dose-dependent manner. Distribution profiles of metals in the soluble fraction of the liver of CeCl3-treated mice analyzed by high performance liquid chromatography/inductively coupled argon plasma-mass spectrometry (HPLC/ICP-MS) demonstrated that the metal bound to MT-I and MT-II was zinc, but not cerium. Administration of CeCl3 caused increases in the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the levels of serum amyloid A (SAA), an acute phase protein. Among inflammatory cytokines examined, interleukin 6 (IL-6) exhibited a marked increase in the serum at 3 h after the CeCl3 administration. In order to evaluate the involvement of IL-6 in the induction of MT by cerium, we examined MT induction by CeCl3 in IL-6 null mice. Both the induction of hepatic MT and the increases in SAA levels were markedly suppressed in IL-6 null mice. These results suggest that IL-6 plays an important role in the induction of hepatic MT by cerium.