Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice.
Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice.
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DOI：
10.1016/j.jhep.2009.10.037
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发表时间：
2010-05
影响因子：
25.7
通讯作者：
Andrew R
中科院分区：
文献类型：
--
作者：
McNeilly AD;Macfarlane DP;O'Flaherty E;Livingstone DE;Mitić T;McConnell KM;McKenzie SM;Davies E;Reynolds RM;Thiesson HC;Skøtt O;Walker BR;Andrew R
下丘脑-垂体-肾上腺轴的抑制发生在肝硬变和胆汁淤积症中，并与胆汁酸浓度升高有关。我们调查了这是否通过胆汁酸通过5-β-还原酶抑制糖皮质激素代谢而损害类固醇清除。在体外研究了胆汁酸对肝亚细胞组分和肝癌细胞糖皮质激素代谢的影响，从而定量测定了5β-还原酶的动力学和转录丰度。随后在饮食操作或胆管结扎后对大鼠的体内代谢进行了检测。最后，对梗阻性黄疸患者的糖皮质激素代谢进行了评估。在大鼠肝细胞浆中，鹅去氧胆酸竞争性抑制5β还原酶(Ki 9.19±0.40μM)，并降低其转录丰度(在H4IiE细胞中)和启动子活性(报告系统，HepG2细胞)。在Wistar大鼠中，日粮鹅去氧胆酸(1%w/w)可抑制肝脏5β还原酶的活性，减少尿3α，5β四氢皮质酮的排泄，减轻肾上腺重量。相反，脱脂饲料抑制胆汁酸水平，提高肝脏5β还原酶活性，添加CDCA降低5β还原酶活性，降低尿中3α，5β皮质酮的活性。大鼠胆汁淤积抑制肝脏5-β-还原酶活性和转录本丰度。在8例梗阻性黄疸患者中，3-α，5-β-四氢皮质醇的相对尿排泄量显著低于健康对照组。这些数据提示胆汁酸在抑制肝糖皮质激素清除中的新作用，其大小足以抑制下丘脑-垂体-肾上腺轴的活动。肝脏胆汁酸升高可能是肝病患者肾上腺功能不全的原因。
Suppression of the hypothalamic–pituitary–adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5β-reductase. The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5β-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5β-reductase (Ki 9.19 ± 0.40 μM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5β-reductase activity, reduced urinary excretion of 3α,5β-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5β-reductase activity, supplementation of the fat-free diet with CDCA reduced 5β-reductase activity, and urinary 3α,5β-reduced corticosterone. Cholestasis in rats suppressed hepatic 5β-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3α,5β-tetrahydrocortisol was significantly lower than in healthy controls. These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic–pituitary–adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease.
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