Regulation of bile acid, cholesterol, and fatty acid synthesis in chicken primary hepatocytes by different concentrations of T0901317, an agonist of liver X receptors
Regulation of bile acid, cholesterol, and fatty acid synthesis in chicken primary hepatocytes by different concentrations of T0901317, an agonist of liver X receptors
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DOI：
10.1016/j.cbpa.2010.10.028
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发表时间：
2011-02-01
影响因子：
2.3
通讯作者：
Kamada, Toshihiko
中科院分区：
文献类型：
--
作者：
Sato, Kan;Kamada, Toshihiko
肝X受体（LXRs）是转录因子核受体家族的成员。它们在胆汁酸和脂肪酸合成等脂质代谢过程中起着至关重要的作用，在哺乳动物胆固醇合成和摄取的调节中也起着次要或有限的作用。然而，在鸟类中，除了知道LXRs参与刺激脂肪酸合成外，对其作用知之甚少。在这项研究中，我们对LXR合成激动剂T0901317处理的鸡原代肝细胞中胆汁酸、胆固醇、脂肪酸合成和VLDL分泌相关基因的表达谱进行了表征。通过添加低浓度（0.01 μ M）的T0901317培养基，刺激鸡胆汁酸合成、mRNA表达和胆汁酸排泄的关键酶——胆固醇7 α羟化酶（CYP7A1）活性。相比之下，高浓度（10 μ M） T0901317培养的细胞中，甾醇调节元件结合蛋白(SREBP)-1、脂肪酸合成酶mRNA和vldl -三酰基甘油水平均高于零浓度或低浓度T0901317培养的细胞。这些结果表明，细胞对这种LXR激动剂的反应与哺乳动物相似。本研究的一项新发现涉及T0901317处理后鸡肝细胞胆固醇合成和摄取调节的变化。当T0901317浓度增加到1.0 μ M时，srebp -2,3-羟基-3-甲基丙二酰辅酶A还原酶（HMGR）和低密度脂蛋白受体（LDLr） mRNA的表达水平随T0901317浓度的增加而增加，但与对照条件下培养的细胞的表达水平相似。这些结果表明，LXRs在鸡肝细胞胆固醇的合成和摄取中起重要作用。与哺乳动物的研究结果不同，在哺乳动物中，LXR激动剂对胆固醇合成的影响在调节细胞固醇稳态中只起很小的作用。(C) 2010爱思唯尔公司版权所有。
Liver X receptors (LXRs) are members of the nuclear receptor family of transcription factors. They play a crucial role in lipid metabolism processes such as bile acid and fatty acid synthesis, as well as minor or limited roles in the regulation of cholesterol synthesis and uptake in mammals. In avian species, however, little is known about the role of LXRs except for the fact that they are involved in the stimulation of fatty acid synthesis. In this study, we characterize the expression profile of genes related to bile acid, cholesterol, and fatty acid synthesis and VLDL secretion in chicken primary hepatocytes treated with T0901317, a synthetic agonist of LXR. The activity of chicken cholesterol 7 alpha hydroxylase (CYP7A1), a key enzyme in bile acid synthesis, mRNA expression, and bile acid excretion, was stimulated by supplementation of the culture medium with a low concentration (0.01 mu M) of T0901317. In contrast, the levels of sterol regulatory element binding protein (SREBP)-1, fatty acid synthase mRNA, and VLDL-triacylglycerol in cells cultured in the presence of a high concentration (10 mu M) of T0901317 were higher than those cultured in zero or low concentrations of T0901317. These results suggest that cellular responses to this LXR agonist were similar to those present in mammals. A novel finding of this study concerned changes to the regulation of cholesterol synthesis and uptake in chicken hepatocytes treated with T0901317. Levels of SREBP-2,3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and low-density lipoprotein receptor (LDLr) mRNA expression increased as a function of increasing T0901317 (up to 1.0 mu M), but remained similar to those in cells cultured under control conditions when the concentration of T0901317 was increased to 10 mu M. These results suggest that LXRs play an important role in cholesterol synthesis and uptake in chicken hepatocytes and, as such, differ to findings in mammals where the effect of LXR agonists on cholesterol synthesis plays only a minor role in the regulation of cellular sterol homeostasis. (C) 2010 Elsevier Inc. All rights reserved.