Lalloyer Fanny, Pedersen Thomas Askov, Gross Barbara, Lestavel Sophie, Yous Saïd, Vallez Emmanuelle, Gustafsson Jan-Ake, Mandrup Susanne, Fiévet Catherine, Staels Bart, Tailleux Anne
University Lille Nord de France, Lille, France.
Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1488-95. doi: 10.1161/ATVBAHA.109.189506. Epub 2009 Jul 10.
Bexarotene (Targretin) is a clinically used antitumoral agent which exerts its action through binding to and activation of the retinoid-X-receptor (RXR). The most frequent side-effect of bexarotene administration is an increase in plasma triglycerides, an independent risk factor of cardiovascular disease. The molecular mechanism behind this hypertriglyceridemia remains poorly understood.
Using wild-type and LXR alpha/beta-deficient mice, we show here that bexarotene induces hypertriglyceridemia and activates hepatic LXR-target genes of lipogenesis in an LXR-dependent manner, hence exerting a permissive effect on RXR/LXR heterodimers. Interestingly, RNA analysis and Chromatin Immunoprecipitation assays performed in the liver reveal that the in vivo permissive effect of bexarotene on the RXR/LXR heterodimer is restricted to lipogenic genes without modulation of genes controlling cholesterol homeostasis.
These findings demonstrate that the hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver.
贝沙罗汀（他扎罗汀）是一种临床使用的抗肿瘤药物，通过与维甲酸X受体（RXR）结合并激活该受体发挥作用。使用贝沙罗汀最常见的副作用是血浆甘油三酯升高，这是心血管疾病的一个独立危险因素。这种高甘油三酯血症背后的分子机制仍知之甚少。
利用野生型和肝X受体α/β缺陷型小鼠，我们在此表明，贝沙罗汀以肝X受体依赖性方式诱导高甘油三酯血症并激活肝脏中参与脂肪生成的肝X受体靶基因，从而对RXR/肝X受体异二聚体发挥允许作用。有趣的是，在肝脏中进行的RNA分析和染色质免疫沉淀试验表明，贝沙罗汀对RXR/肝X受体异二聚体的体内允许作用仅限于脂肪生成基因，而不调节控制胆固醇稳态的基因。
这些发现表明，贝沙罗汀的高甘油三酯血症作用是通过RXR/肝X受体异二聚体发生的，并表明RXR异二聚体可以对肝脏中特定代谢途径的靶基因具有选择性允许作用。
