Zinc supplementation enhances hepatic regeneration by preserving hepatocyte nuclear factor-4α in mice subjected to long-term ethanol administration

Xinqin Kang, Zhenyuan Song, Craig J. McClain, Yujian Kang, Zhanxiang Zhou

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Alcoholic liver disease is associated with sustained liver damage and impaired regeneration, as well as significant zinc deficiency. This study was undertaken to examine whether dietary zinc supplementation could improve liver regeneration by increasing the expression of genes involved in hepatic cellular proliferation in a mouse model of alcoholic liver disease. Adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed alcoholic liver disease as measured by serum alanine transferase activity and histopathological changes. Zinc supplementation to ethanol-exposed mice enhanced liver regeneration as indicated by increased numbers of proliferation cell nuclear antigen (PCNA)-positive and bromodeoxyuridine (BrdU)-labeled hepatocytes. Zinc-enhanced liver regeneration was associated with an increase in hepatocyte nuclear factor-4α (HNF-4α), a liver-enriched, zinc-finger transcription factor. Studies using cultured HepG2 cells showed that zinc deficiency suppressed cell proliferation and cell proliferation-related proteins, including hepatocyte growth factor (HGF), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 1 (IGFBP1), metallothionein (MT), and cyclin D1, as well as HNF-4α. HNF-4α gene silencing inhibited cell proliferation in association with decreased protein levels of IGF-I, IGFBP1, MT, and cyclin D1. The present study provides evidence that zinc supplementation enhances liver regeneration at least in part by HNF-4α through the up-regulation of cell proliferation-related proteins, suggesting that dietary zinc supplementation may have beneficial effects in alcoholic liver disease.

Original languageEnglish (US)
Pages (from-to)916-925
Number of pages10
JournalAmerican Journal of Pathology
Volume172
Issue number4
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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Hepatocyte Nuclear Factor 4
Zinc
Regeneration
Ethanol
Alcoholic Liver Diseases
Liver Regeneration
Cell Proliferation
Liver
Insulin-Like Growth Factor Binding Protein 1
Metallothionein
Cyclin D1
Dietary Supplements
Insulin-Like Growth Factor I
Nuclear Antigens
Proteins
Hepatocyte Growth Factor
Zinc Fingers
Hep G2 Cells
Gene Silencing
Bromodeoxyuridine

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Zinc supplementation enhances hepatic regeneration by preserving hepatocyte nuclear factor-4α in mice subjected to long-term ethanol administration. / Kang, Xinqin; Song, Zhenyuan; McClain, Craig J.; Kang, Yujian; Zhou, Zhanxiang.

In: American Journal of Pathology, Vol. 172, No. 4, 01.01.2008, p. 916-925.

Research output: Contribution to journalArticle

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