Bile Acids as Regulators of Hepatic Lipid and Glucose Metabolism
Bile Acids as Regulators of Hepatic Lipid and Glucose Metabolism
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DOI：
10.1159/000282091
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发表时间：
2010-01-01
影响因子：
2.3
通讯作者：
Wagner, Martin
中科院分区：
文献类型：
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作者：
Trauner, Michael;Claudel, Thierry;Wagner, Martin
除了在饮食脂质吸收和胆固醇稳态中发挥明确的作用外，胆汁酸 (BA) 还充当代谢活性信号分子。重吸收的 BA 的流量经历肠肝循环，与共同吸收的营养物质（例如葡萄糖、脂质）一起到达肝脏，提供协调肝脏甘油三酯 (TG)、葡萄糖和能量稳态的信号。 BA作为具有系统内分泌功能的信号分子，可以激活蛋白激酶A和C以及丝裂原激活的蛋白激酶通路。此外，它们是 G 蛋白偶联 BA 受体 (TGR5/Gpbar-1) 的配体，并激活核受体，例如法尼醇 X 受体 (FXR；NR1H4)。 FXR 及其下游靶标在控制肝脏从头脂肪生成、极低密度脂蛋白-TG 输出和血浆 TG 周转方面发挥着关键作用。 BA 激活的 FXR 和信号转导途径还参与肝糖异生、糖原合成和胰岛素敏感性的调节。通过 TGR5，BA 能够刺激小肠中胰高血糖素样肽-1 的分泌以及棕色脂肪组织和骨骼肌中的能量消耗。 BA 转运失调和 BA 受体信号传导受损可能导致非酒精性脂肪肝 (NAFLD) 的发病机制。因此，BA转运和BA控制的核受体和信号通路是治疗NAFLD的有希望的药物靶点。因此，FXR 和/或 TGR5 配体在 NAFLD 动物模型和临床试点研究中显示出有希望的结果。尽管熊去氧胆酸 (UDCA) 是一种较差的 FXR 和 TGR5 配体，但它可以改善肝脏 ER 应激和胰岛素敏感性。值得注意的是，UDCA（UDCA 的侧链缩短同系物）也不能改善西方饮食喂养的 ApoE(-/-) 小鼠的脂肪肝和动脉粥样硬化。总的来说，这些发现表明 BA 及其受体/信号通路可能是治疗 NAFLD 以及肥胖、糖尿病、血脂异常和动脉硬化等密切相关疾病的一种有前景的方法。版权所有 (C) 2010 S. Karger AG，巴塞尔
Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, bile acids (BA) also act as metabolically active signaling molecules. The flux of reabsorbed BA undergoing enterohepatic circulation, arriving in the liver with the co-absorbed nutrients (e. g. glucose, lipids), provides a signal that coordinates hepatic triglyceride (TG), glucose and energy homeostasis. As signaling molecules with systemic endocrine functions, BA can activate protein kinases A and C as well as mitogen-activated protein kinase pathways. Additionally, they are ligands for a G-protein-coupled BA receptor (TGR5/Gpbar-1) and activate nuclear receptors such as farnesoid X receptor (FXR; NR1H4). FXR and its downstream targets play a key role in the control of hepatic de novo lipogenesis, very-low-density lipoprotein-TG export and plasma TG turnover. BA-activated FXR and signal transduction pathways are also involved in the regulation of hepatic gluconeogenesis, glycogen synthesis and insulin sensitivity. Via TGR5, BA are able to stimulate glucagon-like peptide-1 secretion in the small intestine and energy expenditure in brown adipose tissue and skeletal muscle. Dysregulation of BA transport and impaired BA receptor signaling may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Thus, BA transport and BA-controlled nuclear receptors and signaling pathways are promising drug targets for treatment of NAFLD. As such, FXR and/or TGR5 ligands have shown promising results in animal models of NAFLD and clinical pilot studies. Despite being a poor FXR and TGR5 ligand, ursodeoxycholic acid (UDCA) improves hepatic ER stress and insulin sensitivity. Notably, nor UDCA, a side chain-shortened homologue of UDCA, improves fatty liver and atherosclerosis in Western diet-fed ApoE(-/-) mice. Collectively, these findings suggest that BA and targeting their receptor/signaling pathways may represent a promising approach to treat NAFLD and closely linked disorders such as obesity, diabetes, dyslipidemia and arteriosclerosis. Copyright (C) 2010 S. Karger AG, Basel