FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.
FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.
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DOI：
10.1016/j.cmet.2021.06.012
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发表时间：
2021-08-03
期刊：
影响因子：
29
通讯作者：
de Aguiar Vallim TQ
中科院分区：
文献类型：
--
作者：
Clifford BL;Sedgeman LR;Williams KJ;Morand P;Cheng A;Jarrett KE;Chan AP;Brearley-Sholto MC;Wahlström A;Ashby JW;Barshop W;Wohlschlegel J;Calkin AC;Liu Y;Thorell A;Meikle PJ;Drew BG;Mack JJ;Marschall HU;Tarling EJ;Edwards PA;de Aguiar Vallim TQ
FXR激动剂用于治疗非酒精性脂肪性肝病（NAFLD），部分原因是它们降低了肝脏脂质。在这里，我们表明FXR激动剂GSK2324通过减少吸收和选择性减少脂肪酸合成来控制肝脏脂质。使用全面的脂质组学分析，我们表明小鼠或人类中的FXR激活特异性降低了肝脏中单不饱和脂肪酸和多不饱和脂肪酸（MUFA和PUFA）的水平。MUFA的减少是由于FXR依赖性的Scd 1，Dgat 2和Lpin 1表达的抑制，这是独立于SHP和SREBP 1c。PUFA的FXR依赖性降低是由脂质吸收减少介导的。在饮食中补充胆汁酸可防止GSK 2324处理小鼠的脂质吸收减少，表明FXR通过减少胆汁酸减少吸收。我们使用组织特异性FXR基因敲除小鼠来证明肝脏FXR控制脂肪生成基因，而肠道FXR控制脂质吸收。总之，我们的研究建立了FXR调节肝脏脂质的两种不同途径。核受体FXR降低肝脏甘油三酯以防止NAFLD的发作。Clifford等人证明，FXR的激活通过两种不同的机制降低肝脏甘油三酯。首先，通过胆汁酸依赖性减少肠道脂质吸收，其次，通过选择性改变脂肪生成。
FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids. The nuclear receptor FXR lowers hepatic triglycerides to protect against the onset of NAFLD. Clifford et al. demonstrate that activation of FXR decreases hepatic triglycerides through two distinct mechanisms. First, via bile-acid-dependent decreases in intestinal lipid absorption and second, through selective changes in lipogenesis.
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影响因子：
5.1
作者：
Kleiner DE;Makhlouf HR
通讯作者：
Makhlouf HR
影响因子：
64.8
作者：
Lee, Jae Man;Wagner, Martin;Xiao, Rui;Kim, Kang Ho;Feng, Dan;Lazar, Mitchell A.;Moore, David D.
通讯作者：
Moore, David D.
DOI：
10.1002/hep.29305
发表时间：
2017-12
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Akinrotimi O;Riessen R;VanDuyne P;Park JE;Lee YK;Wong LJ;Zavacki AM;Schoonjans K;Anakk S
通讯作者：
Anakk S
影响因子：
2.7
作者：
Bass, Jonathan Y.;Caravella, Justin A.;Wisely, G. Bruce
通讯作者：
Wisely, G. Bruce
影响因子：
8.6
作者：
Huynh, Kevin;Barlow, Christopher K.;Meikle, Peter J.
通讯作者：
Meikle, Peter J.