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Is Associated with Zinc Protection Against TNF- Hepatotoxicity in Mice
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* Departments of Medicine and Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40202; and Veterans Affairs Medical Center, Louisville, Kentucky 40206
To whom requests for reprints should be addressed at 1 Department of Medicine, University of Louisville School of Medicine, 511 South Floyd Street, MDR 529, Louisville, KY 40202. E-mail: z0zhou01{at}louisville.edu
Hepatocyte nuclear factor-4
(HNF-4), a zinc finger protein, is the most abundant transcription factor in the liver. HNF-4 regulates a large number of genes involved in most aspects of hepatocyte functions. The present study was undertaken to determine the role of HNF-4 in zinc protection against tumor necrosis factor- (TNF-) hepatotoxicity. Mice were treated with murine TNF- via intravenous injection at 20 µg/kg body wt 30 mins after D-galactosamine (D-Gal) sensitization (800 mg/kg body wt). Two doses of zinc sulfate (5 mg elemental zinc/kg body wt) were administered at 36 and 12 hrs before TNF- treatment via subcutaneous injection. TNF- treatment after sensitization induced liver injury as detected by plasma alanine aminotransferase activity and apoptotic cell death in the liver. Zinc pretreatment attenuated TNF-–induced liver injury. Furthermore, TNF-–induced activations of caspase 3 and caspase 8 in the liver were significantly inhibited by zinc pretreatment. The mRNA and protein levels of HNF-4 in the liver were remarkably decreased by TNF- treatment, which was suppressed by zinc. To determine if HNF-4 depletion is involved in D-Gal sensitization to TNF- toxicity, mice were administered either D-Gal or TNF-. Immunohistochemistry demonstrated that HNF-4 depletion in the liver is associated with D-Gal sensitization but not TNF- treatment. To define the link between HNF-4 depletion and TNF-–induced cell death, the effect of silencing the HNF-4 gene by siRNA transfection on TNF- cytotoxicity was determined in HepG2 cells. A lactate dehydrogenase cytotoxicity assay showed that neither TNF- nor HNF-4 siRNA transfection had a toxic effect, but TNF- treatment after HNF-4 siRNA transfection caused HepG2 cell death. These results suggest that zinc protects against TNF- hepatotoxicity, at least partially, through preservation of the zinc finger protein HNF-4.
Key Words: TNF- • • hepatocyte nuclear factor-4 • apoptosis • zinc • liver
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