小柯机器人

美国加州大学Thomas Q. de Aguiar Vallim小组发现，激活FXR可通过胆汁酸依赖性的方式降低脂质吸收从而预防非酒精性脂肪性肝病 (NAFLD)。2021年7月15日，国际学术期刊《细胞-代谢》发表了这一成果。

研究人员发现使用 FXR激活剂 GSK2324 激活FXR可通过减少脂肪吸收和选择性降低脂肪酸合成的方式来控制肝脏脂质。使用全面的脂质组学分析，研究表明小鼠或人类中的FXR的激活特异性降低了单不饱和脂肪酸和多不饱和脂肪酸（MUFA 和 PUFA）在肝脏中的含量。MUFA的减少是由于FXR依赖的Scd1、Dgat2和Lpin1表达受抑制造成的，而与SHP 和SREBP1c无关。多不饱和脂肪酸的FXR依赖性降低是由脂质吸收的降低产生的。

在饮食中补充胆汁酸可防止GSK2324治疗小鼠的脂质吸收减少，这表明FXR 是通过减少胆汁酸减少脂肪吸收。使用组织特异性FXR KO小鼠，研究人员表明肝脏FXR调控脂肪生成基因，而肠道FXR控制脂质吸收。总之，该研究揭示了FXR调控肝脏脂质的两种不同途径。

据悉，FXR 激活剂可用于治疗NAFLD，部分是因为它们可降低肝脏脂肪。

附：英文原文

Title: FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption

Author: Bethan L. Clifford, Leslie R. Sedgeman, Kevin J. Williams, Pauline Morand, Angela Cheng, Kelsey E. Jarrett, Alvin P. Chan, Madelaine C. Brearley-Sholto, Annika Wahlstrm, Julianne W. Ashby, William Barshop, James Wohlschlegel, Anna C. Calkin, Yingying Liu, Anders Thorell, Peter J. Meikle, Brian G. Drew, Julia J. Mack, Hanns-Ulrich Marschall, Elizabeth J. Tarling, Peter A. Edwards, Thomas Q. de Aguiar Vallim

Issue&Volume: 2021-07-15

Abstract: FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in partbecause they reduce hepatic lipids. Here, we show that FXR activation with the FXRagonist GSK2324 controls hepatic lipids via reduced absorption and selective decreasesin fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXRactivation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturatedfatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repressionof Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAsare mediated by decreases in lipid absorption. Replenishing bile acids in the dietprevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXRreduces absorption via decreased bile acids. We used tissue-specific FXR KO mice toshow that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipidabsorption. Together, our studies establish two distinct pathways by which FXR regulateshepatic lipids.

DOI: 10.1016/j.cmet.2021.06.012

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00282-5

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