Laboratory of Lipid Metabolism and Cancer, Department of Translational Pharmacology, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Chieti, Italy.
Cell Metab. 2010 Aug 4;12(2):187-93. doi: 10.1016/j.cmet.2010.07.002.
Several steps of the HDL-mediated reverse cholesterol transport (RCT) are transcriptionally regulated by the nuclear receptors LXRs in the macrophages, liver, and intestine. Systemic LXR activation via synthetic ligands induces RCT but also causes increased hepatic fatty acid synthesis and steatosis, limiting the potential therapeutic use of LXR agonists. During the last few years, the participation of the intestine in the control of RCT has appeared more evident. Here we show that while hepatic-specific LXR activation does not contribute to RCT, intestinal-specific LXR activation leads to decreased intestinal cholesterol absorption, improved lipoprotein profile, and increased RCT in vivo in the absence of hepatic steatosis. These events protect against atherosclerosis in the background of the LDLR-deficient mice. Our study fully characterizes the molecular and metabolic scenario that elects the intestine as a key player in the LXR-driven protective environment against cardiovascular disease.
几种 HDL 介导的胆固醇逆转运 (RCT) 步骤受巨噬细胞、肝脏和肠道中的核受体 LXR 转录调控。通过合成配体对全身 LXR 的激活诱导 RCT，但也会导致肝脏脂肪酸合成和脂肪变性增加，限制了 LXR 激动剂的潜在治疗用途。在过去的几年中，肠道在 RCT 控制中的参与似乎更加明显。在这里，我们发现虽然肝特异性 LXR 激活对 RCT 没有贡献，但肠特异性 LXR 激活导致肠道胆固醇吸收减少，脂蛋白谱改善，并且在 LDLR 缺陷小鼠的背景下体内 RCT 增加。这些事件可预防动脉粥样硬化。我们的研究充分描述了使肠道成为 LXR 驱动的保护心血管疾病环境中的关键因素的分子和代谢情况。
