PhD, Director, Institut National de la Santé et de la Recherche Médicale, Atherosclerosis, Boulevard Du Pr Leclerc, Batiment J&K, Faclte De Medecine De Lille, Lille 59000, France.
Endocrinology. 2013 Oct;154(10):3690-701. doi: 10.1210/en.2013-1263. Epub 2013 Jul 16.
The α-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 in human nor 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.
α-1-酸性糖蛋白/乳白蛋白（ORMs）是亲脂素蛋白家族的成员。在小鼠中由 3 个多态性基因编码（在人中为 2 个，在大鼠中为 1 个），ORMs 在肝细胞中表达，作为急性期蛋白在应激条件下分泌到血浆中。除了作为纳米载体的作用外，ORMs 还参与多种病理生理过程，如免疫抑制、心脏保护和炎症性肠病。核胆汁酸受体法尼醇 X 受体（FXR）调节胆汁酸稳态以及脂质和葡萄糖代谢，是肠肝功能的重要调节剂。在这里，我们报告小鼠肝脏 FXR 缺失会影响亲脂素家族的几个成员的表达，其中 ORMs 被鉴定为 FXR 的直接靶基因。事实上，在鼠 Orm1 启动子的上游鉴定到一个 FXR 反应元件，肝 FXR 而非回肠 FXR 可以结合并在体外和体内激活 ORM 表达。然而，ORMs 的调节具有种属特异性，因为 ORM 簇既不受人源也不受大鼠细胞系中的 FXR 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未在人或大鼠 ORM 基因簇附近检测到任何 FXR 反应元件。因此，胆汁酸及其同源核受体 FXR 是 ORM 表达的调节剂，这可能对 FXR 控制特定物种的代谢和炎症具有重要意义，因为附睾白色脂肪组织中促炎基因的表达依赖于肝脏 FXR 的激活。
