University of Perugia, Department of Surgical and Biomedical Sciences, Perugia, Italy.
University of Naples Federico II, Department of Pharmacy, Naples, Italy.
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct;1864(10):1422-1437. doi: 10.1016/j.bbalip.2019.07.006. Epub 2019 Jul 17.
Obeticholic acid (OCA) is a farnesoid-X-receptor (FXR) ligand, shown effective in reducing steatosis and fibrosis in NASH patients. However, OCA causes major side effects including pruritus, while increases the risk for liver decompensation in cirrhotic patients. Ursodeoxycholic acid (UDCA), is a safe and unexpensive bile acid used in the treatment of liver disorders whose mechanism of action is poorly defined. Here we have compared the effects of OCA and UDCA in a mouse model of NASH. In mice exposed to a diet rich in fat/cholesterol and fructose (HFD-F), treatment with OCA or UDCA effectively prevented body weight gain, insulin resistance, as demonstrated by OGTT, and AST plasma levels. After 12 weeks HFD-F mice developed liver microvesicular steatosis, inflammation and mild fibrosis, increased expression of inflammatory (TNFα, IL6, F4/80) and fibrosis (αSma, Col1α1, Tgfβ) markers, reduced liver expression of FXR, dysregulated liver FXR signaling and elevated levels of Tauro-α and β-muricholic acid (T-α and βMCA), two FXR antagonists in mice. Both compounds prevented these changes and improved liver histopathology. OCA reduced primary bile acid synthesis worsening the T-CA/T-βMCA ratio. UDCA effectively transactivated GPBAR1 in vitro. By RNAseq analysis we found that among over 2400 genes modulated by the HFD-F, only 32 and 60 genes were modulated by OCA and UDCA, with only 3 genes (Dbp, Adh7, Osgin1) being modulated by both agents. Both agents partially prevented the intestinal dysbiosis. CONCLUSIONS: UDCA is a GPBAR1 ligand and exerts beneficial effects in a rodent model of NASH by activating non-overlapping pathway with OCA.
奥贝胆酸（OCA）是法尼醇 X 受体（FXR）配体，已被证明可有效减少 NASH 患者的脂肪变性和纤维化。然而，OCA 会引起严重的副作用，包括瘙痒，同时增加肝硬化患者肝失代偿的风险。熊去氧胆酸（UDCA）是一种安全且廉价的用于治疗肝脏疾病的胆汁酸，其作用机制尚不清楚。在此，我们比较了 OCA 和 UDCA 在 NASH 小鼠模型中的作用。在暴露于高脂肪/胆固醇和果糖饮食（HFD-F）的小鼠中，OCA 或 UDCA 的治疗可有效预防体重增加、胰岛素抵抗，如 OGTT 和 AST 血浆水平所示。在 12 周 HFD-F 喂养后，小鼠发生肝脏微泡性脂肪变性、炎症和轻度纤维化，炎症（TNFα、IL6、F4/80）和纤维化（αSma、Col1α1、Tgfβ）标志物表达增加，FXR 表达减少，肝 FXR 信号通路失调，Tauro-α 和 β-鼠胆酸（T-α 和 βMCA）水平升高，两种 FXR 拮抗剂在小鼠中。两种化合物均能预防这些变化并改善肝脏组织病理学。OCA 减少初级胆汁酸合成，恶化 T-CA/T-βMCA 比值。UDCA 可有效地在体外激活 GPBAR1。通过 RNAseq 分析，我们发现，在 HFD-F 调节的 2400 多个基因中，只有 32 和 60 个基因被 OCA 和 UDCA 调节，只有 3 个基因（Dbp、Adh7、Osgin1）被两种药物共同调节。两种药物均部分预防了肠道菌群失调。结论：UDCA 是一种 GPBAR1 配体，通过激活与 OCA 不重叠的途径，在 NASH 啮齿动物模型中发挥有益作用。
