Tumor necrosis factor-α-independent downregulation of hepatic cholesterol 7α-hydroxylase gene in mice treated with lead nitrate

Abstract

We previously reported that lead nitrate (LN), an inducer of hepatic tumor necrosis factor-α (TNF-α), downregulated gene expression of cholesterol 7α-hydroxylase. Herein, to clarify the role of TNF-α in LN-induced downregulation of cholesterol 7α-hydroxylase, effects of LN on gene expression of hepatic cholesterol 7α-hydroxylase (Cyp7a1) in TNF-α-knockout (KO) and TNF-α-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-α protein in either WT or KO mice were below the detection limit, although expression levels of the TNF-α 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-1β protein, which is known to be a suppressor of the cholesterol 7α-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 α, retinoid X receptor α, fetoprotein transcription factor, and hepatocyte nuclear factor 4α) 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-α-dependent pathway and might occur mainly through an IL-1β-dependent pathway. © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.