Matsukuma Karen E, Wang Li, Bennett Mary K, Osborne Timothy F
Department of Molecular Biology and Biochemistry, School of Biological Sciences and Center for Diabetes Research and Treatment, University of California, Irvine, CA 92697-3900, USA.
J Biol Chem. 2007 Jul 13;282(28):20164-71. doi: 10.1074/jbc.M702895200. Epub 2007 May 22.
Liver X receptor (LXR) activates fatty acid synthase (FAS) gene expression through binding to a DR-4 element in the promoter. We show that a distinct nuclear receptor half-site 21 bases downstream of the DR-4 element is also critical for the response of FAS to LXR but is not involved in LXR binding to DNA. This half-site specifically binds liver receptor homologue-1 (LRH-1) in vitro and in vivo, and we show LRH-1 is required for maximal LXR responsiveness of the endogenous FAS gene as well as from promoter reporter constructs. We also demonstrate that LRH-1 stimulation of the FAS LXR response is blocked by the addition of small heterodimer partner (SHP) and that FAS mRNA is overexpressed in SHP knock-out animals, providing evidence that FAS is an in vivo target of SHP repression. Taken together, these findings identify the first direct lipogenic gene target of LRH-1/SHP repression and provide a mechanistic explanation for bile acid repression of FAS and lipogenesis recently reported by others.
肝X受体（LXR）通过与启动子中的DR-4元件结合来激活脂肪酸合酶（FAS）基因的表达。我们发现，在DR-4元件下游21个碱基处的一个独特的核受体半位点对于FAS对LXR的反应也至关重要，但不参与LXR与DNA的结合。该半位点在体外和体内均能特异性结合肝脏受体同源物-1（LRH-1），并且我们发现内源性FAS基因以及启动子报告基因构建体对LXR的最大反应需要LRH-1。我们还证明，添加小异二聚体伴侣（SHP）可阻断LRH-1对FAS LXR反应的刺激，并且FAS mRNA在SHP基因敲除动物中过表达，这表明FAS是SHP抑制作用的体内靶点。综上所述，这些发现确定了LRH-1/SHP抑制作用的首个直接脂肪生成基因靶点，并为其他人最近报道的胆汁酸对FAS和脂肪生成的抑制作用提供了机制解释。
