<br>长期给予核胆汁酸受体 FXR 激动剂可预防 Abcb4-/- 小鼠的自发性肝癌发生。,Scientific Reports

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长期给予核胆汁酸受体 FXR 激动剂可预防 Abcb4-/- 小鼠的自发性肝癌发生。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Sep-11 , DOI: 10.1038/s41598-017-11549-7
Marica Cariello ₁ , Claudia Peres _{1,

2} , Roberta Zerlotin _{1,

2} , Emanuele Porru ₃ , Carlo Sabbà ₁ , Aldo Roda ₃ , Antonio Moschetta _{1,

4}

Affiliation

胆汁酸 (BA) 信号传导的改变与肝毒性相关。法尼醇 X 受体 (FXR) 是一种核受体，可转录调节 BA 稳态。 FXR 消融的小鼠由于高毒性 BA 水平而出现肝癌 (HCC)。 Abcb4 消融的小鼠在胆管内积聚有毒 BA，并出现 HCC。我们之前已经表明，转基因 VP16-FXR 嵌合体对 FXR 的肠道特异性激活能够减少 BA 池大小并预防 HCC。在这里，我们通过给予双 FXR/膜 G 蛋白偶联受体 (TGR5) 激动剂 INT-767 (6α-乙基-3α,7α,23-三羟基-24-nor-5β-cholan-23) 15 个月来测试化学 FXR 激活-硫酸盐）至 Fxr ^-/-和 Abcb4 ^-/-小鼠。 INT-767 给药显着减少了 HCC 的数量和大小。相比之下，在喂食或不喂食 INT-767 的 Fxr ^-/-小鼠中，未观察到 HCC 肿瘤数量和大小的变化。值得注意的是，INT-767 保留了肝实质，改善了肝功能并下调了促炎细胞因子。此外，在 Abcb4 ^-/-小鼠中，INT-767 通过减少胶原蛋白表达和沉积来预防纤维化。因此，长期激活 FXR 能够减少 BA 池，重新编程 BA 代谢并预防 HCC。这些数据为解决 FXR 激活在与 BA 相关的 HCC 发展疾病中的真正治疗潜力提供了动力。

"点击查看英文标题和摘要"

Long-term Administration of Nuclear Bile Acid Receptor FXR Agonist Prevents Spontaneous Hepatocarcinogenesis in Abcb4-/- Mice.

Altered bile acid (BA) signaling is associated with hepatotoxicity. The farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates BA homeostasis. Mice with FXR ablation present hepatocarcinoma (HCC) due to high toxic BA levels. Mice with Abcb4 ablation accumulate toxic BA within the bile ducts and present HCC. We have previously shown that intestinal specific activation of FXR by transgenic VP16-FXR chimera is able to reduce BA pool size and prevent HCC. Here we tested chemical FXR activation by administering for 15 months the dual FXR/ membrane G protein-coupled receptor (TGR5) agonist INT-767 (6α-ethyl-3α,7α,23-trihydroxy-24-nor-5β-cholan-23-sulphate) to Fxr^-/- and Abcb4^-/- mice. HCC number and size were significantly reduced by INT-767 administration. In contrast, no changes in HCC tumor number and size were observed in Fxr^-/- mice fed with or without INT-767. Notably, INT-767 preserved the hepatic parenchyma, improved hepatic function and down-regulated pro-inflammatory cytokines. Moreover, in Abcb4^-/- mice INT-767 prevented fibrosis by reducing collagen expression and deposition. Thus, long term activation of FXR is able to reduce BA pool, reprogram BA metabolism and prevent HCC. These data provide the impetus to address the bona fide therapeutic potential of FXR activation in disease with BA-associated development of HCC.

更新日期：2017-09-11

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