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Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice

机译:肝LXRα表达对于小鼠体内胆固醇稳态和逆向胆固醇转运至关重要

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摘要

Liver X receptors (LXRα and LXRβ) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Small molecule agonists of LXR activity are therefore of great therapeutic interest. However, the finding that such agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. To investigate whether this might be true, we performed gene targeting to selectively delete LXRα in hepatocytes. Liver-specific deletion of LXRα in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRα for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRα increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRα, indicating that the ability of agonists to reduce cardiovascular disease did not require an increase in cholesterol excretion. Furthermore, when non-atherogenic mice were treated with synthetic LXR agonists, liver-specific deletion of LXRα eliminated the detrimental effect of increased plasma triglycerides, while the beneficial effect of increased plasma HDL was unaltered. In sum, these observations suggest that therapeutic strategies that bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease.
机译:肝X受体(LXRα和LXRβ)是胆固醇和脂质代谢的重要调节剂,在动物模型中,它们的活化已显示出抑制心血管疾病和减少动脉粥样硬化的作用。因此,LXR活性的小分子激动剂具有极大的治疗意义。然而,这种激动剂也促进肝脂肪生成的发现导致了这样的想法,即从治疗的角度来看,肝LXR活性是不可取的。为了研究这是否正确,我们进行了基因靶向以选择性删除肝细胞中的LXRα。小鼠中肝脏特异性LXRα的缺失大大降低了胆固醇的逆向转运,胆固醇分解代谢和胆固醇排泄,从而揭示了肝脏LXRα对全身胆固醇体内稳态的至关重要性。此外,在促动脉粥样硬化的背景下,肝脏特异性LXRα的缺失会增加动脉粥样硬化,从而揭示了肝脏LXR活性在限制心血管疾病中的重要作用。然而,在缺乏肝LXRα的情况下,合成LXR激动剂仍会引起抗动脉粥样硬化活性,表明该激动剂减少心血管疾病的能力不需要增加胆固醇排泄。此外,当用合成的LXR激动剂对非动脉粥样硬化小鼠进行治疗时,肝脏特异性LXRα的缺失消除了血浆甘油三酸酯增加的有害作用,而血浆HDL的有益作用没有改变。总之,这些观察结果表明,绕过肝脏或限制肝LXRs激活的治疗策略仍应有益于心血管疾病的治疗。

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