Geniposide reduces cholesterol accumulation and increases its excretion by regulating the FXR-mediated liver-gut crosstalk of bile acids
Geniposide reduces cholesterol accumulation and increases its excretion by regulating the FXR-mediated liver-gut crosstalk of bile acids
复制标题
京尼平苷通过调节 FXR 介导的胆汁酸肝肠串扰来减少胆固醇积累并增加其排泄
DOI：
10.1016/j.phrs.2020.104631
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发表时间：
2020-02-01
影响因子：
9.3
通讯作者：
Wang, Li
中科院分区：
文献类型：
--
作者：
Liu, Jinxin;Li, Yan;Wang, Li
高胆固醇血症是威胁人体健康的主要危险因素，京尼平苷已被发现具有降血脂功能。然而，其潜在机制尚不清楚。在本研究中，我们首次证实了京尼平苷对C57BL/6和ApoE（-/-）小鼠（i.p, 50 mg/kg/d）的降血脂功能。然后通过组织形态学分析肝脏或动脉脂质积累。通过肝脏RNA-seq和生物分子分析，分析京尼平苷对胆汁酸代谢的影响。在机制上，我们采用FXR激动剂GW4064来验证京尼平苷对人HepG2和Caco2细胞的作用机制。正如预期的那样，京尼平苷降低了血浆和肝脏中的脂质积聚。此外，用京尼平苷治疗hcd喂养的ApoE（-/-）小鼠的动脉粥样硬化斑块缩小。分子分析表明，京尼平苷通过灭活FXR介导的胆汁酸负反馈调节，加速肝脏胆汁酸合成，导致胆固醇逆向转运和胆固醇分解代谢增强。此外，京尼平苷减少了回肠fxr介导的胆汁酸重吸收，导致胆汁酸排泄增加。本研究指出，京尼平苷对fxr介导的胆汁酸和京尼平苷肝肠串音的调节作用可能是维持胆固醇稳态的一种新策略。
Hypercholesterolemia is the main risk factor to threaten human health and geniposide has been found to have hypolipidemic functions. However, its underlying mechanism is not clear. In this study, we firstly confirmed the hypolipidemic functions of geniposide in C57BL/6 and ApoE(-/-) mice (i.p, 50 mg/kg/d). Then hepatic or arterial lipid accumulation was analyzed through histomorphology. Moreover, the effects of geniposide on the bile acid metabolism were analyzed by the hepatic RNA-seq and biological molecular analysis. Mechanistically, GW4064, an FXR agonist, was carried out to verify the mechanisms of geniposide in human HepG2 and Caco2 cells. As expected, geniposide decreased the lipid accumulations both in plasma and liver. Morever, the atherosclerotic plaque shrank in HCD-fed ApoE(-/-) mice with geniposide treatment. The molecular analysis revealed that geniposide accelerated the hepatic synthesis of bile acids through inactivating the negative feedback regulation of bile acids mediated by FXR, led to the enhancive reverse cholesterol transport and cholesterol catabolism. What's more, geniposide reduced ileal FXR-mediated reabsorption of bile acids, resulting in the increasing excretion of bile acids. Our study pointed out the regulatory functions of geniposide on FXR-mediated liver-gut crosstalk of bile acids and geniposide might be a novel strategy for maintaining cholesterol homeostasis.