Chen Yen-Hsu, Hong I-Chu, Kuo Kung-Kai, Hsu Hseng-Kuang, Hsu Chin
Department of Internal Medicine, Division of Infectious Diseases, Kaohsiung Medical University, Kaohsiung, Taiwan.
Shock. 2007 Jul;28(1):65-70. doi: 10.1097/shk.0b013e31802ec5d2.
Sepsis causes intrahepatic cholestasis and leads to hepatic failure. However, the pathophysiology of hepatic events is unclear. Expression of rat hepatic bile acid coenzyme A-amino acid N-acyltransferase (rBAT), a major enzyme for the conjugation of bile acids, is significantly decreased during sepsis. rBAT transcriptional regulation is mainly by a heterodimer of farnesoid-X receptor (FXR) and retinoid-X receptor-alpha (RXR-alpha) via the inverted repeat 1 sequence. During sepsis, nuclear receptors and translocation of RXR-alpha from cytosol to nucleus decrease. The purpose of this study was to further clarify the mechanisms of RXR-alpha-mediated rBAT regulation during polymicrobial sepsis and with dexamethasone treatment. Polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP). Liver tissues obtained 3, 6, 9, and 18 h after CLP were studied, and hepatocytes were isolated from rats with sepsis. Post-CLP decreases were observed in mRNA levels of rBAT (6 h), protein levels of rBAT (6 h), RXR-alpha (6 h), and FXR (9 h). DNA binding activity of FXR/RXR significantly decreased at 6 h after CLP. Dexamethasone reversed sepsis-inhibited RXR-alpha expression and the binding activity of FXR/RXR to rBAT DNA as well as rBAT protein expression. The results suggest that suppression of rBAT occurs at the transcriptional level, and the decrease in RXR-alpha by septic insult may play a critical role in rBAT suppression at the early stage of polymicrobial sepsis.
脓毒症可导致肝内胆汁淤积并引发肝衰竭。然而，肝脏相关事件的病理生理学尚不清楚。大鼠肝胆汁酸辅酶A - 氨基酸N - 酰基转移酶（rBAT）是胆汁酸结合的主要酶，其在脓毒症期间表达显著降低。rBAT的转录调控主要通过法尼醇X受体（FXR）和视黄醇X受体α（RXR - α）经由反向重复序列1形成的异二聚体来实现。在脓毒症期间，核受体以及RXR - α从胞质溶胶向细胞核的转位均减少。本研究的目的是进一步阐明在多微生物脓毒症及地塞米松治疗过程中RXR - α介导的rBAT调控机制。通过盲肠结扎和穿刺（CLP）诱导大鼠发生多微生物脓毒症。对CLP术后3、6、9和18小时获取的肝脏组织进行研究，并从脓毒症大鼠中分离肝细胞。观察到CLP术后rBAT的mRNA水平（6小时）、rBAT的蛋白水平（6小时）、RXR - α（6小时）和FXR（9小时）均下降。CLP术后6小时，FXR/RXR的DNA结合活性显著降低。地塞米松逆转了脓毒症抑制的RXR - α表达以及FXR/RXR与rBAT DNA的结合活性和rBAT蛋白表达。结果表明，rBAT的抑制发生在转录水平，脓毒症损伤导致的RXR - α减少可能在多微生物脓毒症早期rBAT的抑制中起关键作用。
