Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
J Clin Invest. 2012 May;122(5):1688-99. doi: 10.1172/JCI59817. Epub 2012 Apr 9.
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.
肝 X 受体 (LXRα 和 LXRβ) 是胆固醇和脂质代谢的重要调节剂，其激活已被证明可抑制动物模型中的心血管疾病和减少动脉粥样硬化。因此，LXR 活性的小分子激动剂具有很大的治疗意义。然而，这些激动剂也促进肝内脂质生成的发现导致了从治疗角度来看肝 LXR 活性是不可取的想法。为了研究这是否可能是真的，我们进行了基因靶向以选择性地在肝细胞中删除 LXRα。在小鼠中，LXRα 的肝特异性缺失显著降低了胆固醇逆转运、胆固醇分解代谢和胆固醇排泄，揭示了肝 LXRα 对全身胆固醇稳态的至关重要性。此外，在促动脉粥样硬化背景下，LXRα 的肝特异性缺失增加了动脉粥样硬化，揭示了肝 LXR 活性在限制心血管疾病方面的重要功能。然而，在缺乏肝 LXRα 的情况下，合成 LXR 激动剂仍然具有抗动脉粥样硬化活性，表明激动剂降低心血管疾病的能力不需要增加胆固醇排泄。此外，当非动脉粥样硬化小鼠用合成 LXR 激动剂治疗时，LXRα 的肝特异性缺失消除了增加血浆甘油三酯的有害影响，而增加血浆 HDL 的有益影响则没有改变。总之，这些观察结果表明，绕过肝脏或限制肝 LXR 激活的治疗策略对于治疗心血管疾病仍应是有益的。
