Preservation of Hepatocyte nuclear factor-4α is associated with zinc protection against TNF-α hepatotoxicity in mice

Zhanxiang Zhou, Xinqin Kang, Youchun Jiang, Zhenyuan Song, Wenke Feng, Craig J. McClain, Yujian Kang

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Hepatocyte nuclear factor-4α (HNF-4α), a zinc finger protein, is the most abundant transcription factor in the liver. HNF-4α regulates a large number of genes involved in most aspects of hepatocyte functions. The present study was undertaken to determine the role of HNF-4α in zinc protection against tumor necrosis factor-α (TNF-α) hepatotoxicity. Mice were treated with murine TNF-α 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-α treatment via subcutaneous injection. TNF-α treatment after sensitization induced liver injury as detected by plasma alanine aminotransferase activity and apoptotic cell death in the liver. Zinc pretreatment attenuated TNF-α-induced liver injury. Furthermore, TNF-α-induced activations of caspase 3 and caspase 8 in the liver were significantly inhibited by zinc pretreatment. The mRNA and protein levels of HNF-4α in the liver were remarkably decreased by TNF-α treatment, which was suppressed by zinc. To determine if HNF-4α depletion is involved in D-Gal sensitization to TNF-α toxicity, mice were administered either D-Gal or TNF-α. Immunohistochemistry demonstrated that HNF-4α depletion in the liver is associated with D-Gal sensitization but not TNF-α treatment. To define the link between HNF-4α depletion and TNF-α-induced cell death, the effect of silencing the HNF-4α gene by siRNA transfection on TNF-α cytotoxicity was determined in HepG2 cells. A lactate dehydrogenase cytotoxicity assay showed that neither TNF-α nor HNF-4α siRNA transfection had a toxic effect, but TNF-α treatment after HNF-4α siRNA transfection caused HepG2 cell death. These results suggest that zinc protects against TNF-α hepatotoxicity, at least partially, through preservation of the zinc finger protein HNF-4α.

Original languageEnglish (US)
Pages (from-to)622-628
Number of pages7
JournalExperimental Biology and Medicine
Volume232
Issue number5
StatePublished - May 1 2007
Externally publishedYes

Fingerprint

Hepatocyte Nuclear Factor 4
Zinc
Tumor Necrosis Factor-alpha
Liver
Galactosamine
Cell death
Small Interfering RNA
Transfection
Cell Death
Zinc Fingers
Hep G2 Cells
Cytotoxicity
Genes
Zinc Sulfate
Therapeutics
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Preservation of Hepatocyte nuclear factor-4α is associated with zinc protection against TNF-α hepatotoxicity in mice. / Zhou, Zhanxiang; Kang, Xinqin; Jiang, Youchun; Song, Zhenyuan; Feng, Wenke; McClain, Craig J.; Kang, Yujian.

In: Experimental Biology and Medicine, Vol. 232, No. 5, 01.05.2007, p. 622-628.

Research output: Contribution to journalArticle

Zhou, Zhanxiang ; Kang, Xinqin ; Jiang, Youchun ; Song, Zhenyuan ; Feng, Wenke ; McClain, Craig J. ; Kang, Yujian. / Preservation of Hepatocyte nuclear factor-4α is associated with zinc protection against TNF-α hepatotoxicity in mice. In: Experimental Biology and Medicine. 2007 ; Vol. 232, No. 5. pp. 622-628.
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