The Hepatic Orosomucoid/α1-Acid Glycoprotein Gene Cluster Is Regulated by the Nuclear Bile Acid Receptor FXR
The Hepatic Orosomucoid/α1-Acid Glycoprotein Gene Cluster Is Regulated by the Nuclear Bile Acid Receptor FXR
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DOI：
10.1210/en.2013-1263
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发表时间：
2013-10-01
期刊：
影响因子：
4.8
通讯作者：
Lefebvre, Philippe
中科院分区：
文献类型：
--
作者：
Porez, Geoffrey;Gross, Barbara;Lefebvre, Philippe
α-1-酸性糖蛋白/乳清类粘蛋白（ORM）是脂质运载蛋白家族的成员。ORM在小鼠中由3个多态性基因编码（人中2个，大鼠中1个），在肝细胞中表达，并在应激条件下作为急性期蛋白分泌到血浆中。除了纳米载体的作用外，ORM还参与了几种病理生理过程，如免疫抑制，心脏保护和炎症性肠病。核胆汁酸受体法尼酯X受体（FXR）调节胆汁酸稳态和脂质及葡萄糖代谢，是肠肝功能的重要调节剂。在这里，我们报告，小鼠肝脏FXR缺失影响脂质运载蛋白家族的几个成员的表达，其中ORM被确定为直接FXR靶基因。事实上，小鼠Orm 1启动子上游的FXR反应元件被鉴定为肝脏而不是回肠的FXR可以在体外和体内结合并激活ORM表达。然而，由于ORM簇既不受人也不受大鼠细胞系的FXR调节，因此ORM以种特异性方式调节。与这些数据一致，FXR基因组结合位点的染色质免疫沉淀测序分析在人或大鼠ORM基因簇附近未检测到任何FXR反应元件。因此，胆汁酸和它们的同源核受体FXR是ORM表达的调节剂，具有FXR对物种特异性代谢和炎症控制的潜在影响，因为附睾白色脂肪组织中促炎基因的表达依赖于肝脏FXR活化。
The alpha-1-acid glycoprotein/orosomucoids (ORMs) are members of the lipocalin protein family. Encoded by 3 polymorphic genes in mouse (2 in man, 1 in rat), ORMs are expressed in hepatocytes and function as acute-phase proteins secreted in plasma under stressful conditions. In addition to their role of nanocarrier, ORMs are involved in several pathophysiological processes such as immunosuppression, cardioprotection, and inflammatory bowel disease. The nuclear bile acid receptor farnesoid X receptor (FXR) regulates bile acid homeostasis and lipid and glucose metabolism and is an important modulator of enterohepatic functions. Here we report that hepatic FXR deletion in mice affects the expression of several members of the lipocalin family, among which ORMs are identified as direct FXR target genes. Indeed, a FXR response element upstream of the mouse Orm1 promoter was identified to which hepatic, but not ileal, FXR can bind and activate ORM expression in vitro and in vivo. However, ORMs are regulated in a species-specific manner because the ORM cluster is regulated by FXR neither inhumannor rat cell lines. Consistent with these data, chromatin immunoprecipitation sequencing analysis of the FXR genomic binding sites did not detect any FXR response element in the vicinity of the human or rat ORM gene cluster. Thus, bile acids and their cognate nuclear receptor, FXR, are regulators of ORM expression, with potential implications for the species-specific metabolic and inflammation control by FXR because the expression of the proinflammatory genes in epididymal white adipose tissue was dependent on liver FXR activation.