Lehrke Michael, Lebherz Corinna, Millington Segan C, Guan Hong-Ping, Millar John, Rader Daniel J, Wilson James M, Lazar Mitchell A
Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Cell Metab. 2005 May;1(5):297-308. doi: 10.1016/j.cmet.2005.04.005.
The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. Liver X receptors (LXRs) are oxysterol sensors that are required for normal cholesterol and triglyceride homeostasis, yet synthetic LXR agonists produce undesirable hypertriglyceridemia. Here we report a previously unrecognized role for hepatic LXRalpha in the links between diet, serum lipids, and atherosclerosis. A modest increase in hepatic LXRalpha worsened serum lipid profiles in LDL-receptor null mice fed normal chow but had the opposite effect on lipids and afforded strong protection against atherosclerosis on a Western diet. The beneficial effect of hepatic LXRalpha was abrogated by a synthetic LXR agonist, which activated SREBP-1c and its target genes. Thus, the interplay between diet and hepatic LXRalpha is a critical determinant of serum lipid profiles and cardiovascular risk, and selective modulation of LXR target genes in liver can ameliorate hyperlipidemia and cardiovascular disease.
高胆固醇/高脂肪的西方饮食助长了动脉粥样硬化性心血管疾病的流行，而这种疾病是工业化国家的主要死因。肝脏X受体（LXRs）是氧化甾醇传感器，对于正常的胆固醇和甘油三酯稳态是必需的，但合成的LXR激动剂会产生不良的高甘油三酯血症。在此，我们报告肝脏LXRα在饮食、血脂与动脉粥样硬化之间的联系中存在一个此前未被认识到的作用。肝脏LXRα适度增加会使喂食普通饲料的低密度脂蛋白受体缺失小鼠的血脂谱恶化，但对血脂有相反的作用，并且在西方饮食条件下能提供强大的抗动脉粥样硬化保护。肝脏LXRα的有益作用被一种合成的LXR激动剂消除，该激动剂激活了固醇调节元件结合蛋白-1c（SREBP-1c）及其靶基因。因此，饮食与肝脏LXRα之间的相互作用是血脂谱和心血管风险的关键决定因素，并且在肝脏中对LXR靶基因进行选择性调节可以改善高脂血症和心血管疾病。
