Joseph Sean B, Laffitte Bryan A, Patel Parthive H, Watson Michael A, Matsukuma Karen E, Walczak Robert, Collins Jon L, Osborne Timothy F, Tontonoz Peter
Department of Pathology and Laboratory Medicine, the Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
J Biol Chem. 2002 Mar 29;277(13):11019-25. doi: 10.1074/jbc.M111041200. Epub 2002 Jan 14.
The nuclear receptors LXRalpha and LXRbeta have been implicated in the control of lipogenesis and cholesterol homeostasis. Ligand activation of these receptors in vivo induces expression of the LXR target gene SREBP-1c and increases plasma triglyceride levels. Expression of fatty acid synthase (FAS), a central enzyme in de novo lipogenesis and an established target of the SREBP-1 pathway, is also induced by LXR ligands. The effects of LXR ligands on FAS expression have been proposed to be entirely secondary to the induction of SREBP-1c. We demonstrate here that LXRs regulate FAS expression through direct interaction with the FAS promoter as well as through activation of SREBP-1c expression. Induction of FAS expression in HepG2 cells by LXR ligands is reduced, but not abolished, under conditions where SREBP processing is suppressed. Moreover, LXR ligands induce FAS expression in CHO-7 cells without altering expression of SREBP-1. We demonstrate that in addition to tandem SREBP sites, the FAS promoter contains a high affinity binding site for the LXR/RXR heterodimer that is conserved in diverse animal species including birds, rodents, and humans. The LXR and SREBP binding sites independently confer LXR responsiveness on the FAS promoter, and maximal induction requires both transcription factors. Transient elevation of plasma triglyceride levels in mice treated with a synthetic LXR agonist correlates with transient induction of hepatic FAS expression. These results indicate that the LXR signaling pathway modulates FAS expression through distinct but complementary mechanisms and suggest that the FAS gene may be a critical target in the control of lipogenesis by LXRs.
核受体肝X受体α（LXRα）和肝X受体β（LXRβ）参与脂肪生成和胆固醇稳态的调控。这些受体在体内的配体激活可诱导LXR靶基因固醇调节元件结合蛋白-1c（SREBP-1c）的表达，并增加血浆甘油三酯水平。脂肪酸合酶（FAS）是从头脂肪生成中的关键酶，也是SREBP-1途径的既定靶点，其表达也可被LXR配体诱导。LXR配体对FAS表达的影响被认为完全是SREBP-1c诱导的继发效应。我们在此证明，LXRs通过与FAS启动子直接相互作用以及激活SREBP-1c表达来调节FAS表达。在SREBP加工被抑制的条件下，LXR配体对HepG2细胞中FAS表达的诱导作用降低，但并未消除。此外，LXR配体可在CHO-7细胞中诱导FAS表达，而不改变SREBP-1的表达。我们证明，除了串联的SREBP位点外，FAS启动子还含有一个LXR/RXR异二聚体的高亲和力结合位点，该位点在包括鸟类、啮齿动物和人类在内的多种动物物种中保守。LXR和SREBP结合位点独立赋予FAS启动子LXR反应性，最大诱导需要两种转录因子。用合成LXR激动剂处理的小鼠血浆甘油三酯水平的短暂升高与肝脏FAS表达的短暂诱导相关。这些结果表明，LXR信号通路通过不同但互补的机制调节FAS表达，并提示FAS基因可能是LXRs控制脂肪生成的关键靶点。
