Clock mutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet
Clock mutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet
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DOI：
10.1152/ajpendo.00061.2007
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发表时间：
2008-01-01
影响因子：
5.1
通讯作者：
Shibata, Shigenobu
中科院分区：
文献类型：
--
作者：
Kudo, Takashi;Kawashima, Mihoko;Shibata, Shigenobu
肝脏中的胆固醇 (CH) 稳态由 CH 合成酶（例如 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR)）和分解代谢酶（例如细胞色素 P-450、家族 7、亚家族 A 和多肽 1 (CYP7A1)）调节。由于生物钟控制这些酶的基因表达，因此这些基因在肝脏中表现出昼夜节律。在这项研究中，我们研究了含有 CH 和/或胆酸 (CA) 的饮食与小鼠肝脏中 Hmgcr、低密度脂蛋白受体 (Ldlr) 和 Cyp7a1 基因表达的昼夜节律调节之间的关系。 4 周的 CA 饮食降低并最终消除了这些基因的昼夜节律表达。在时钟突变小鼠的肝脏中，不仅周期同源物 2（果蝇）（Per2）和脑和肌肉 arnt 样蛋白 1（Bmal1）等时钟基因，而且 Hmgcr、Ldlr 和 Cyp7a1 等时钟控制基因也显示出减少和心律失常的表达模式。与野生型小鼠相比，饲喂含有 CA 或 CH + CA 饮食的小鼠的肝脏中 Cyp7a1 基因表达的降低在 Clock 突变体小鼠中显着，并且在 Clock 突变体小鼠中肝脏 CH 积累明显较高。相比之下，不含 CA 的 CH 饮食仅升高野生型和 Clock 突变小鼠的 Cyp7a1 表达。目前的研究结果表明，正常的生物钟功能对于调节小鼠肝脏中 CH 稳态非常重要，特别是与含有高 CH 和 CA 的饮食结合使用。
Cholesterol (CH) homeostasis in the liver is regulated by enzymes of CH synthesis such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and catabolic enzymes such as cytochrome P-450, family 7, subfamily A, and polypeptide 1 (CYP7A1). Since a circadian clock controls the gene expression of these enzymes, these genes exhibit circadian rhythm in the liver. In this study, we examined the relationship between a diet containing CH and/or cholic acid (CA) and the circadian regulation of Hmgcr, low-density lipoprotein receptor (Ldlr), and Cyp7a1 gene expression in the mouse liver. A 4-wk CA diet lowered and eventually abolished the circadian expression of these genes. Not only clock genes such as period homolog 2 (Drosophila) (Per2) and brain and muscle arnt-like protein-1 (Bmal1) but also clock-controlled genes such as Hmgcr, Ldlr, and Cyp7a1 showed a reduced and arrhythmic expression pattern in the liver of Clock mutant mice. The reduced gene expression of Cyp7a1 in mice fed a diet containing CA or CH + CA was remarkable in the liver of Clock mutants compared with wild-type mice, and high liver CH accumulation was apparent in Clock mutant mice. In contrast, a CH diet without CA only elevated Cyp7a1 expression in both wild-type and Clock mutant mice. The present findings indicate that normal circadian clock function is important for the regulation of CH homeostasis in the mouse liver, especially in conjunction with a diet containing high CH and CA.