ToxSci Advance Access published online on July 27, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi267
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1 Laboratory of Animal Gene Function, Department of Physiology and Gene Regulation, Institute of Insect and Animal Sciences, National Institute of Agrobiological Sciences, Kannondai 2-1-2, Tsukuba 305-8602, Japan
* To whom correspondence should be addressed. We previously reported that lead nitrate (LN), an inducer of hepatic tumor necrosis factor-
Received May 15, 2005
Accepted July 22, 2005
Systems Toxicology
Tumor Necrosis Factor-
-Independent Down-Regulation of Hepatic Cholesterol 7-Hydroxylase Gene in Mice Treated with Lead Nitrate
2 Department of Molecular Biology and Immunology, Institute of Insect and Animal Sciences, National Institute of Agrobiological Sciences, Kannondai 2-1-2, Tsukuba 305-8602, Japan
3 Department of Molecular Toxicology and COE Program for the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan
Misaki Kojima, E-mail: misaki{at}affrc.go.jp
Abstract 
(TNF-), down-regulated gene expression of cholesterol 7-hydroxylase. Herein, to clarify the role of TNF- in LN-induced down-regulation of cholesterol 7-hydroxylase, effects of LN on gene expression of hepatic cholesterol 7-hydroxylase (Cyp7a1) in TNF--knockout (KO) and TNF--wild type (WT) mice were comparatively examined. Gene expression of hepatic Cyp7a1 in both WT and KO mice decreased to less than 5% of the corresponding controls at 6-12 h after treatment with LN (100 µmol/kg body weight, iv). Levels of hepatic TNF- protein in either WT or KO mice were below the detection limit, although expression levels of the TNF- gene markedly increased at 6 h in WT mice by LN-treatment, but not in KO mice. On the other hand, levels of hepatic IL-1
protein, which is known to be a suppressor of the cholesterol 7-hydroxylase gene in hamsters, in both WT and KO mice were significantly increased 3-6 h after LN-treatment. Furthermore, LN-induced down-regulation of the Cyp7a1 gene did not necessarily result from altered gene expression of hepatic transcription factors, including positive regulators (liver X receptor , retinoid X receptor , fetoprotein transcription factor and hepatocyte nuclear factor 4) and a negative regulator small heterodimer partner responsible for expression of the Cyp7a1 gene. The present findings indicated that LN-induced down-regulation of the Cyp7a1 gene in mice did not necessarily occur through a TNF--dependent pathway and might occur mainly through an IL-1-dependent pathway.; IL-1; liver; mouse.
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