Fondazione Italiana Fegato, AREA Science Park Basovizza, SS14 km 163.5, 34149, Trieste, Italy.
Intercept Pharmaceutical, Inc, 10 Hudson Yards 37th Floor, 10001, New York, NY, USA.
Sci Rep. 2020 Feb 3;10(1):1699. doi: 10.1038/s41598-020-58562-x.
Pharmacological treatments for non-alcoholic steatohepatitis (NASH) are still unsatisfactory. Fibrosis is the most significant predictor of mortality and many anti-fibrotic agents are under evaluation. Herein, we assessed in vitro the effects of the FXR agonist obeticholic acid (OCA) and the dual FXR/TGR5 agonist INT-767 in a well-established co-culture NASH model. Co-cultures of human hepatoma and hepatic stellate (HSCs) cells were exposed to free fatty acids (FFAs) alone or in combination with OCA or INT-767. mRNA expression of HSCs activation markers and FXR engagement were evaluated at 24, 96 and 144 hours. Collagen deposition and metalloproteinase 2 and 9 (MMP2-9) activity were compared to tropifexor and selonsertib. FFAs induced collagen deposition and MMP2-9 activity reduction. Co-treatment with OCA or INT-767 did not affect ACTA2 and COL1A1 expression, but significantly reduced FXR and induced SHP expression, as expected. OCA induced a dose-dependent reduction of collagen and induced MMP2-9 activity. Similarly, INT-767 induced collagen reduction at 96 h and a slight increase in MMP2-9. Tropifexor and Selonsertib were also effective in collagen reduction but showed no modulation of MMP2-9. All tested compounds reduced collagen deposition. OCA exerted a more potent and long-lasting effect, mainly related to modulation of collagen turn-over and MMP2-9 activity.
非酒精性脂肪性肝炎（NASH）的药物治疗仍然不尽如人意。纤维化是死亡率的最重要预测因素，许多抗纤维化药物正在评估中。在此，我们在体外评估了 FXR 激动剂奥贝胆酸（OCA）和双重 FXR/TGR5 激动剂 INT-767 在成熟的共培养 NASH 模型中的作用。将人肝癌细胞和肝星状细胞（HSCs）共培养物暴露于游离脂肪酸（FFAs）中，或与 OCA 或 INT-767 联合暴露。在 24、96 和 144 小时评估 HSCs 激活标志物和 FXR 结合的 mRNA 表达。与 tropifexor 和 selonsertib 相比，比较了胶原沉积和金属蛋白酶 2 和 9（MMP2-9）的活性。FFAs 诱导胶原沉积和 MMP2-9 活性降低。OCA 或 INT-767 的联合治疗并未影响 ACTA2 和 COL1A1 的表达，但如预期的那样，显著降低了 FXR 并诱导了 SHP 的表达。OCA 诱导胶原呈剂量依赖性减少，并诱导 MMP2-9 活性增加。类似地，INT-767 在 96 小时诱导胶原减少，并略微增加 MMP2-9。tropifexor 和 selonsertib 也能有效减少胶原，但对 MMP2-9 没有调节作用。所有测试的化合物都减少了胶原沉积。OCA 发挥了更强和更持久的作用，主要与胶原转化和 MMP2-9 活性的调节有关。
