Yale Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Hepatology. 2011 Feb;53(2):548-57. doi: 10.1002/hep.24047. Epub 2010 Dec 10.
Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Despite limited benefits, ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for cholestatic disorders. Retinoic acid (RA) is a ligand for nuclear receptors that modulate bile salt homeostasis. RA also possesses immunomodulatory effects and is used to treat acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis. To test whether the supplementation of RA with UDCA is superior to UDCA alone for treating cholestasis, male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 days and were treated with phosphate-buffered saline (PBS), UDCA, all-trans retinoic acid (atRA), or UDCA and atRA by gavage. Treatment with UDCA and atRA substantially improved animal growth rates, significantly reduced liver fibrosis and bile duct proliferation, and nearly eliminated liver necrosis after BDL. Reductions in the bile salt pool size and liver hydroxyproline content were also seen with treatment with atRA or atRA and UDCA versus PBS and UDCA. Furthermore, atRA and UDCA significantly reduced liver messenger RNA and/or protein expression of transforming growth factor β1 (Tgf-β1), collagen 1a1 (Col1A1), matrix metalloproteinase 2 (Mmp2), cytokeratin 19, α-smooth muscle actin (α-SMA), cytochrome P450 7A1 (Cyp7a1), tumor necrosis factor α, and interleukin-β1. The molecular mechanisms of this treatment were also assessed in human hepatocytes, hepatic stellate cells, and LX-2 cells. atRA alone or in combination with UDCA greatly repressed CYP7A1 expression in human hepatocytes and significantly inhibited COL1A1, MMP2, and α-SMA expression and/or activity in primary human hepatic stellate cells and LX-2 cells. Furthermore, atRA reduced TGF-β1-induced Smad2 phosphorylation in LX-2 cells.
Our findings indicate that the addition of RA to UDCA reduces the bile salt pool size and liver fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases.
胆汁淤积可导致肝细胞死亡、纤维化、肝硬化，最终导致肝功能衰竭。尽管熊去氧胆酸（UDCA）的疗效有限，但它仍是唯一获得美国食品和药物管理局批准用于治疗胆汁淤积性疾病的药物。维 A 酸（RA）是一种核受体配体，可调节胆汁盐动态平衡。RA 还具有免疫调节作用，用于治疗急性早幼粒细胞白血病和炎症性疾病，如银屑病、痤疮和类风湿性关节炎。为了测试 RA 联合 UDCA 是否优于单独使用 UDCA 治疗胆汁淤积，雄性 Sprague-Dawley 大鼠接受胆总管结扎（BDL）14 天，并通过灌胃接受磷酸盐缓冲盐水（PBS）、UDCA、全反式维 A 酸（atRA）或 UDCA 和 atRA 治疗。UDCA 和 atRA 治疗可显著提高动物生长速度，显著减少肝纤维化和胆管增生，并在 BDL 后几乎消除肝坏死。用 atRA 或 atRA 和 UDCA 治疗还可减少胆汁盐池大小和肝羟脯氨酸含量，与 PBS 和 UDCA 相比。此外，atRA 和 UDCA 还显著降低了肝信使 RNA 和/或转化生长因子 β1（Tgf-β1）、胶原 1a1（Col1A1）、基质金属蛋白酶 2（Mmp2）、细胞角蛋白 19、α-平滑肌肌动蛋白（α-SMA）、细胞色素 P450 7A1（Cyp7a1）、肿瘤坏死因子-α和白细胞介素-β1 的表达。还在人肝细胞、肝星状细胞和 LX-2 细胞中评估了这种治疗的分子机制。atRA 单独或与 UDCA 联合使用可大大抑制人肝细胞中 CYP7A1 的表达，并显著抑制原代人肝星状细胞和 LX-2 细胞中 COL1A1、MMP2 和 α-SMA 的表达和/或活性。此外，atRA 降低了 LX-2 细胞中 TGF-β1 诱导的 Smad2 磷酸化。
我们的研究结果表明，RA 联合 UDCA 可减少胆汁盐池大小和肝纤维化，可能是治疗胆汁淤积性疾病的有效辅助治疗方法。
