Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists.
Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists.
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DOI：
10.1021/acschembio.2c00057
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发表时间：
2022-04
影响因子：
4
通讯作者：
K. Griffett;Matthew E. Hayes;Gonzalo Bedia-Diaz;K. Appourchaux;Ryan Sanders;Michael P Boeckman;Thomas Koelblen;Jinsong Zhang;I. Schulman;Bahaa Elgendy;T. Burris
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文献类型：
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作者：
K. Griffett;Matthew E. Hayes;Gonzalo Bedia-Diaz;K. Appourchaux;Ryan Sanders;Michael P Boeckman;Thomas Koelblen;Jinsong Zhang;I. Schulman;Bahaa Elgendy;T. Burris
高血压和循环胆固醇水平升高与心血管疾病风险增加有关。肝脏X受体（LXRs）是脂肪生成和胆固醇转运的调节因子，并且已被证实为动脉粥样硬化治疗的潜在治疗靶点。然而，开发LXR激动剂以减少心血管疾病的努力由于不良临床结果相关的肝脂肪生成增加和低密度脂蛋白（LDL）胆固醇升高而失败（C）。在这里，我们报告说，LXR反向激动剂是有效的，在降低血浆LDL胆固醇和甘油三酯在几种高脂血症模型，包括Ldlr空小鼠模型动脉粥样硬化。机制研究表明，LXR直接调节肠道中Soat 2酶的表达，Soat 2酶直接负责循环脂质的再摄取或排泄。口服肠道特异性LXR反向激动剂导致肠道中Soat 2表达减少，并有效降低循环LDL胆固醇和甘油三酯水平，而不调节外周中的LXR靶基因。总之，我们的研究强调了肠道限制性分子通过肠道LXR-Soat 2轴治疗高脂血症和动脉粥样硬化的治疗潜力。
Hyperlipidemia and increased circulating cholesterol levels are associated with increased cardiovascular disease risk. The liver X receptors (LXRs) are regulators of de novo lipogenesis and cholesterol transport and have been validated as potential therapeutic targets for the treatment of atherosclerosis. However, efforts to develop LXR agonists to reduce cardiovascular diseases have failed due to poor clinical outcomes-associated increased hepatic lipogenesis and elevated low-density lipoprotein (LDL) cholesterol (C). Here, we report that LXR inverse agonists are effective in lowering plasma LDL cholesterol and triglycerides in several models of hyperlipidemia, including the Ldlr null mouse model of atherosclerosis. Mechanistic studies demonstrate that LXR directly regulates the expression of Soat2 enzyme in the intestine, which is directly responsible for the re-uptake or excretion of circulating lipids. Oral administration of a gut-specific LXR inverse agonist leads to reduction of Soat2 expression in the intestine and effectively lowers circulating LDL cholesterol and triglyceride levels without modulating LXR target genes in the periphery. In summary, our studies highlight the therapeutic potential of the gut-restricted molecules to treat hyperlipidemia and atherosclerosis through the intestinal LXR-Soat2 axis.