Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt.
Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt.
Biochem Pharmacol. 2021 Apr;186:114497. doi: 10.1016/j.bcp.2021.114497. Epub 2021 Mar 4.
Despite the recent substantial progress in the treatment of hepatocellular carcinoma (HCC) from viral etiology, non-alcoholic steatohepatitis (NASH) is on a trajectory to become the fastest growing indication for HCC-related liver transplantation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily with multifaceted roles in several metabolic disorders, particularly NASH. Its role as a tumor suppressor was also highlighted. Herein, we investigated the effect of obeticholic acid (OCA), as an FXR agonist, on NASH-associated HCC (NASH-HCC) animal model induced by diethylnitrosamine and high fat choline-deficient diet, exploring the potential impact on the suppressor of cytokine signaling 3 (SOCS3)/Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway. Results indicated that OCA treatment upregulated FXR and its key mediator, small heterodimer partner (SHP), with remarkable amelioration in the dysplastic foci observed in the NASH-HCC group. This was paralleled with noticeable downregulation of alpha fetoprotein along with reduction in interferon gamma and transforming growth factor beta-1 hepatic levels besides caspase-3 and p53 upregulation. Moreover, sirtuin-1 (SIRT-1), a key regulator of FXR that controls the regenerative response of the liver, was elevated following OCA treatment. Modulation in the SOCS3/Jak2/STAT3 signaling axis was also reported. In conclusion, OCA attenuated the development and progression of NASH-dependent HCC possibly by interfering with SOCS3/Jak2/STAT3 pathway suggesting the potential use of FXR activators in NASH-related disorders, even at later stages of the disease, to impede its progression to the more deteriorating condition of HCC.
尽管近年来在治疗病毒性肝细胞癌 (HCC) 方面取得了重大进展，但非酒精性脂肪性肝炎 (NASH) 正成为与 HCC 相关的肝移植增长最快的适应症。法尼醇 X 受体 (FXR) 是核受体超家族的成员，在多种代谢紊乱中具有多方面的作用，特别是 NASH。它作为肿瘤抑制因子的作用也得到了强调。在此，我们研究了 FXR 激动剂奥贝胆酸 (OCA) 对二乙基亚硝胺和高脂肪胆碱缺乏饮食诱导的 NASH 相关 HCC (NASH-HCC) 动物模型的影响，探讨了其对细胞因子信号转导抑制因子 3 (SOCS3)/Janus 激酶 2 (Jak2)/信号转导和转录激活因子 3 (STAT3) 通路的潜在影响。结果表明，OCA 治疗可上调 FXR 及其关键介质小异二聚体伴侣 (SHP)，可显著改善 NASH-HCC 组观察到的发育不良灶。这与甲胎蛋白的显著下调以及干扰素 γ 和转化生长因子 β-1 肝水平的降低以及 caspase-3 和 p53 的上调平行。此外，FXR 的关键调节剂 SIRT-1 (SIRT-1) 在 OCA 治疗后升高，SIRT-1 可控制肝脏的再生反应。SOCS3/Jak2/STAT3 信号轴的调节也有报道。总之，OCA 可能通过干扰 SOCS3/Jak2/STAT3 通路来减轻 NASH 依赖性 HCC 的发生和发展，这表明 FXR 激活剂在 NASH 相关疾病中的潜在用途，甚至在疾病的晚期，也可以阻止其进展为更严重的 HCC 状态。
