Involvement of Interleukin-1 in Lead Nitrate-Induced Hypercholesterolemia in Mice
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Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and cholesterol 7α-hydroxylase (Cyp7a1) are rate-limiting enzymes for cholesterol biosynthesis and catabolism, respectively. Involvement of inflammatory cytokines, particularly interleukin-1 (IL-1), in alterations of <i>HMGR</i> and <i>Cyp7a1</i> gene expression during development of lead nitrate (LN)-induced hypercholesterolemia was examined in IL-1α/β-knockout (IL-1-KO) and wild-type (WT) mice. Lead nitrate treatment of WT mice led to not only a marked downregulation of the <i>Cyp7a1</i> gene at 6—12 h, but also a significant upregulation of the <i>HMGR</i> gene at 12 h. However, such changes were not observed at significant levels in IL-1-KO mice, although a slight, transient downregulation of the <i>Cyp7a1</i> gene and a minimal upregulation of the <i>HMGR</i> gene occurred at 6 h and 24 h, respectively. Consequently, LN treatment led to development of hypercholesterolemia at 24 h in WT mice, but not in IL-1-KO mice. Furthermore, in WT mice, significant LN-mediated increases were observed at 3—6 h in hepatic IL-1 levels, which can modulate gene expression of <i>Cyp7a1</i> and <i>HMGR</i>. These findings indicate that, in mice, LN-mediated increases in hepatic IL-1 levels contribute, at least in part, to altered expressions of <i>Cyp7a1</i> and <i>HMGR</i> genes, and eventually to hypercholesterolemia development.
- Biological and Pharmaceutical Bulletin
Biological and Pharmaceutical Bulletin 35(2), 246-250, 2012
The Pharmaceutical Society of Japan