Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany.
Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany.
FASEB J. 2024 Aug 31;38(16):e23889. doi: 10.1096/fj.202400733R.
Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell-line LX-2 and in vivo using male bile duct-ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha-smooth muscle actin expression in LX-2 cells. In vivo, GSK805 significantly decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being.
胆汁淤积性肝病，如原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC），可导致炎症和严重的肝损伤，治疗选择有限。本研究评估了反向 RORγt 激动剂 GSK805 的疗效，分别在体外使用肝星状细胞系 LX-2 和体内使用雄性胆管结扎 BALB/c 小鼠进行评估。体外实验中，0.3μM 的 GSK805 可降低 LX-2 细胞中α-平滑肌肌动蛋白的表达。在体内，GSK805 可显著降低胆汁淤积性肝脏中 IL-23R、TNF-α 和 IFN-γ 的表达。尽管肝脏中 GSK805 的浓度很高，但未观察到纤维化有明显减少。GSK805 可显著增加血液中转氨酶和丙氨酸转氨酶的活性，而谷氨酸脱氢酶、碱性磷酸酶和胆红素的水平没有明显增加。重要的是，GSK805 既不会增加动物的痛苦评分，也不会显著降低体重、挖洞活动或筑巢行为。这些结果表明，通过每日口服可实现 GSK805 在肝脏中的高浓度，并且该药物可调节胆汁淤积小鼠的炎症，而不会损害动物的健康。
