ToxSci Advance Access originally published online on July 27, 2005
Toxicological Sciences 2005 87(2):537-542; doi:10.1093/toxsci/kfi267
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Tumor Necrosis Factor-
-Independent Downregulation of Hepatic Cholesterol 7-Hydroxylase Gene in Mice Treated with Lead Nitrate
* 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; 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; 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
Received May 15, 2005; accepted July 22, 2005
We previously reported that lead nitrate (LN), an inducer of hepatic tumor necrosis factor-
(TNF-), downregulated gene expression of cholesterol 7-hydroxylase. Herein, to clarify the role of TNF- in LN-induced downregulation 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. In contrast, in both WT and KO mice, levels of hepatic IL-1ß protein, which is known to be a suppressor of the cholesterol 7-hydroxylase gene in hamsters, were significantly increased 3–6 h after LN treatment. Furthermore, LN-induced downregulation 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 downregulation of the Cyp7a1 gene in mice did not necessarily occur through a TNF-–dependent pathway and might occur mainly through an IL-1ß–dependent pathway.
Key Words: lead nitrate; Cyp7a1; TNF-; IL-1ß; liver; mouse.