Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.
Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.
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DOI：
10.1016/j.mce.2014.02.003
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发表时间：
2014-05-05
影响因子：
4.1
通讯作者：
Ayers SD
中科院分区：
文献类型：
--
作者：
Lammel Lindemann JA;Angajala A;Engler DA;Webb P;Ayers SD
甲状腺激素 (TH) 通过作用于肝脏中的 TH 受体 β1 (TRβ1) 来调节代谢基因组，从而调节血清胆固醇。在啮齿类动物中，TH 调节的一个重要步骤涉及 Cyp7a1 的诱导，Cyp7a1 是细胞色素 P450 家族中的一种酶，可增强胆固醇向胆汁酸的转化，并在血清胆固醇水平的调节中发挥至关重要的作用。然而，目前的模型表明，Cyp7a1 已经失去了对人类 TH 做出反应的能力。最近一项合成 TH 模拟物的研究促使我们重新研究 TH 对人类肝细胞中胆固醇代谢基因的影响，该研究表明血清胆固醇的降低伴随着人类胆汁酸合成标记物的增加。在这里，我们发现 TH 对胆固醇代谢基因的影响在小鼠肝脏、小鼠和人类肝脏原代细胞以及人类肝细胞系中几乎相同。此外，Cyp7a1 是一个直接的 TR 靶基因，通过其启动子中的一组不同的反应元件对生理 TR 水平做出反应。这些发现表明，THs 在人类和啮齿动物实验模型中以类似的方式调节胆固醇向胆汁酸的转化，并且激素信号通路的操纵可以提供增强人类患者 Cyp7a1 活性的策略。
Thyroid hormone (TH) modulates serum cholesterol by acting on TH receptor β1 (TRβ1) in liver to regulate metabolic gene sets. In rodents, one important TH regulated step involves induction of Cyp7a1, an enzyme in the cytochrome P450 family, which enhances cholesterol to bile acid conversion and plays a crucial role in regulation of serum cholesterol levels. Current models suggest, however, that Cyp7a1 has lost the capacity to respond to THs in humans. We were prompted to re-examine TH effects on cholesterol metabolic genes in human liver cells by a recent study of a synthetic TH mimetic which showed that serum cholesterol reductions were accompanied by increases in a marker for bile acid synthesis in humans. Here, we show that TH effects upon cholesterol metabolic genes are almost identical in mouse liver, mouse and human liver primary cells and human hepatocyte cell lines. Moreover, Cyp7a1 is a direct TR target gene that responds to physiologic TR levels through a set of distinct response elements in its promoter. These findings suggest that THs regulate cholesterol to bile acid conversion in similar ways in humans and rodent experimental models and that manipulation of hormone signaling pathways could provide a strategy to enhance Cyp7a1 activity in human patients.
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影响因子：
3.7
作者：
Lin JZ;Sieglaff DH;Yuan C;Su J;Arumanayagam AS;Firouzbakht S;Cantu Pompa JJ;Reynolds FD;Zhou X;Cvoro A;Webb P
通讯作者：
Webb P
影响因子：
13.5
作者：
Ellis, E;Goodwin, B;Einarsson, C
通讯作者：
Einarsson, C
影响因子：
--
作者：
Gullberg, H;Rudling, M;Vennström, B
通讯作者：
Vennström, B
DOI：
10.1016/0005-2760(94)90068-x
发表时间：
1994-10-06
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM
影响因子：
--
作者：
NESS, GC;PENDLETON, LC;ZHAO, ZH
通讯作者：
ZHAO, ZH
影响因子：
4.8
作者：
Hashimoto, K;Cohen, RN;Wondisford, FE
通讯作者：
Wondisford, FE