Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
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DOI：
10.1038/nature04330
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发表时间：
2006-01-26
期刊：
影响因子：
64.8
通讯作者：
Auwerx, J
中科院分区：
文献类型：
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作者：
Watanabe, M;Houten, SM;Auwerx, J
虽然胆汁酸（BAs）长期以来一直被认为是膳食脂质吸收和胆固醇代谢所必需的，但近年来BAs作为信号分子的重要作用已经出现。BA激活促分裂原活化蛋白激酶途径（1，2），是G蛋白偶联受体（GPCR）TGR 5的配体（3，4），并激活核激素受体，如法尼醇X受体α（FXR-α; NR 1H 4）（5-7）。FXR-α通过控制基因的表达，如抑制其他核受体活性的短异源二聚体伴侣（SHP; NR 0 B2）（8，9），调节BA的肝肠循环和生物合成。FXR-α介导的SHP诱导也是肝脂肪酸和甘油三酯生物合成以及固醇调节元件结合蛋白1c介导的极低密度脂蛋白产生下调的基础（10）。这表明BA可能能够作为一般代谢整合剂发挥超出BA稳态控制的功能。在这里，我们表明，给小鼠施用BA增加了棕色脂肪组织的能量消耗，防止肥胖和胰岛素抵抗。BAs的这种新的代谢效应严重依赖于环AMP依赖性甲状腺激素激活酶2型碘甲状腺原氨酸脱碘酶（D2）的诱导，因为它在D2（-/-）小鼠中丢失。用BA处理褐色脂肪细胞和人骨骼肌细胞增加D2活性和耗氧量。这些作用不依赖于FXR-α，而是由BA与G蛋白偶联受体TGR 5结合引起的cAMP产生增加介导。在啮齿动物和人类中，最重要的产热组织是这种机制的特异性靶向，因为它们共表达D2和TGR 5。因此，BA-TGR 5- cAMP - D2信号传导途径是微调能量稳态的关键机制，其可以被靶向以改善代谢控制。
While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways(1,2), are ligands for the G-protein-coupled receptor ( GPCR) TGR5(3,4) and activate nuclear hormone receptors such as farnesoid X receptor alpha ( FXR-alpha; NR1H4)(5-7). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2)(8,9) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c(10). This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2(-/-) mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA - TGR5 - cAMP - D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.