Animal Genome Research Unit, Agrogenomics Research Center, National Institute of Agrobiological Sciences, Tsukuba, Japan.
Biol Pharm Bull. 2012;35(2):246-50. doi: 10.1248/bpb.35.246.
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 HMGR and Cyp7a1 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 Cyp7a1 gene at 6-12 h, but also a significant upregulation of the HMGR 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 Cyp7a1 gene and a minimal upregulation of the HMGR 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 Cyp7a1 and HMGR. These findings indicate that, in mice, LN-mediated increases in hepatic IL-1 levels contribute, at least in part, to altered expressions of Cyp7a1 and HMGR genes, and eventually to hypercholesterolemia development.
肝脏 3-羟-3-甲基戊二酰辅酶 A 还原酶（HMGR）和胆固醇 7α-羟化酶（Cyp7a1）分别是胆固醇生物合成和分解代谢的限速酶。白细胞介素-1（IL-1）等炎症细胞因子参与了硝酸铅（LN）诱导的高胆固醇血症发展过程中 HMGR 和 Cyp7a1 基因表达的改变，本研究在 IL-1α/β 基因敲除（IL-1-KO）和野生型（WT）小鼠中进行了检测。LN 处理 WT 小鼠不仅导致 Cyp7a1 基因在 6-12 h 时明显下调，而且在 12 h 时 HMGR 基因显著上调。然而，在 IL-1-KO 小鼠中并未观察到这种变化，尽管 Cyp7a1 基因在 6 h 和 HMGR 基因在 24 h 时出现轻微、短暂的下调和最小程度的上调。因此，LN 处理导致 WT 小鼠在 24 h 时发生高胆固醇血症，但在 IL-1-KO 小鼠中未发生。此外，在 WT 小鼠中，在 3-6 h 时观察到肝内 IL-1 水平显著升高，这可以调节 Cyp7a1 和 HMGR 的基因表达。这些发现表明，在小鼠中，LN 介导的肝内 IL-1 水平升高至少部分导致 Cyp7a1 和 HMGR 基因表达的改变，并最终导致高胆固醇血症的发展。
