Staels B, van Tol A, Skretting G, Auwerx J
Department of Developmental Biology, Gasthuisberg, Katholieke Universiteit Leuven, Belgium.
J Lipid Res. 1992 May;33(5):727-35.
Plasma lipoprotein metabolism is influenced by several factors that may act by regulating the expression of proteins involved in lipoprotein metabolism, such as lecithin:cholesterol acyltransferase (LCAT). We determined the influence of several hormones and hypolipidemic drugs on hepatic LCAT gene expression and plasma LCAT activity. Liver LCAT mRNA levels were resistant to regulation by the hormones ethinylestradiol, L-thyroxine, hydrocortisone, or by the hypolipidemic drugs probucol, simvastatin, and nicotinic acid. In contrast, hepatic LCAT mRNA levels decreased to 67%, 64%, and 46% of the control levels after treatment with the fibric acid derivatives clofibrate, gemfibrozil, and fenofibrate, respectively. Fenofibrate lowered liver LCAT mRNA levels in a dose-dependent manner, which was paralleled by a decrease in plasma LCAT activity to 54% of the controls at a dose of 0.5% (w/w) in rat chow. The decrease in liver LCAT mRNA levels was maximal after 1 day, whereas the fall in plasma LCAT activity trailed by 2 days. Cessation of treatment with fenofibrate restored liver LCAT mRNA levels to control levels within 1 week. The transcription rate of the LCAT gene decreased by 25% in nuclei isolated from fenofibrate-treated rat liver, thereby indicating that hepatic LCAT gene expression is, at least partly, regulated at a transcriptional level. In contrast to the liver, brain and testis LCAT mRNA levels remained constant after treatment with fenofibrate, indicating that fibrates regulate LCAT gene expression in a tissue-selective manner.
血浆脂蛋白代谢受多种因素影响，这些因素可能通过调节参与脂蛋白代谢的蛋白质（如卵磷脂胆固醇酰基转移酶（LCAT））的表达来发挥作用。我们确定了几种激素和降血脂药物对肝脏LCAT基因表达和血浆LCAT活性的影响。肝脏LCAT mRNA水平对炔雌醇、L-甲状腺素、氢化可的松等激素或普罗布考、辛伐他汀和烟酸等降血脂药物的调节具有抗性。相比之下，用氯贝丁酯、吉非贝齐和非诺贝特等纤维酸衍生物处理后，肝脏LCAT mRNA水平分别降至对照水平的67%、64%和46%。非诺贝特以剂量依赖的方式降低肝脏LCAT mRNA水平，在大鼠饲料中添加0.5%（w/w）的非诺贝特时，血浆LCAT活性相应降低至对照水平的54%。肝脏LCAT mRNA水平在1天后降至最低，而血浆LCAT活性的下降则滞后2天。停止使用非诺贝特治疗后，肝脏LCAT mRNA水平在1周内恢复至对照水平。从非诺贝特处理的大鼠肝脏分离的细胞核中，LCAT基因的转录率降低了25%，这表明肝脏LCAT基因表达至少部分在转录水平受到调节。与肝脏不同，用非诺贝特处理后，脑和睾丸的LCAT mRNA水平保持不变，这表明纤维酸衍生物以组织选择性方式调节LCAT基因表达。
