11β-羟甾类脱氢酶-1 通过调节肝脏中的脂肪酸转运蛋白-5 参与胆汁酸的动态平衡。
11β-Hydroxysteroid dehydrogenase-1 is involved in bile acid homeostasis by modulating fatty acid transport protein-5 in the liver of mice.
机构信息
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Centre for Endocrinology Diabetes and Metabolism (CEDAM), Institute of Biomedical Research, Medical School Building, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
出版信息
Mol Metab. 2014 May 2;3(5):554-64. doi: 10.1016/j.molmet.2014.04.008. eCollection 2014 Aug.
11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) plays a key role in glucocorticoid receptor (GR) activation. Besides, it metabolizes some oxysterols and bile acids (BAs). The GR regulates BA homeostasis; however, the impact of impaired 11β-HSD1 activity remained unknown. We profiled plasma and liver BAs in liver-specific and global 11β-HSD1-deficient mice. 11β-HSD1-deficiency resulted in elevated circulating unconjugated BAs, an effect more pronounced in global than liver-specific knockout mice. Gene expression analyses revealed decreased expression of the BA-CoA ligase Fatp5, suggesting impaired BA amidation. Reduced organic anion-transporting polypeptide-1A1 (Oatp1a1) and enhanced organic solute-transporter-β (Ostb) mRNA expression were observed in livers from global 11β-HSD1-deficient mice. The impact of 11β-HSD1-deficiency on BA homeostasis seems to be GR-independent because intrahepatic corticosterone and GR target gene expression were not substantially decreased in livers from global knockout mice. Moreover, Fatp5 expression in livers from hepatocyte-specific GR knockout mice was unchanged. The results revealed a role for 11β-HSD1 in BA homeostasis.
11β-羟类固醇脱氢酶-1（11β-HSD1）在糖皮质激素受体（GR）激活中起着关键作用。此外，它还代谢一些氧化固醇和胆汁酸（BAs）。GR 调节 BA 动态平衡；然而，11β-HSD1 活性受损的影响仍不清楚。我们对肝脏特异性和全身性 11β-HSD1 缺陷小鼠的血浆和肝脏 BAs 进行了分析。11β-HSD1 缺陷导致循环中非结合型 BAs 水平升高，这种效应在全身性而非肝脏特异性敲除小鼠中更为明显。基因表达分析显示 BA-CoA 连接酶 Fatp5 的表达降低，表明 BA 酰胺化受损。观察到全身性 11β-HSD1 缺陷小鼠肝脏中的有机阴离子转运多肽 1A1（Oatp1a1）mRNA 表达降低和有机溶质转运体-β（Ostb）mRNA 表达增强。11β-HSD1 缺陷对 BA 动态平衡的影响似乎与 GR 无关，因为全身性敲除小鼠肝脏内的肝内皮质酮和 GR 靶基因表达没有明显降低。此外，肝细胞特异性 GR 敲除小鼠肝脏中的 Fatp5 表达没有变化。结果表明 11β-HSD1 在 BA 动态平衡中起作用。
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