Investigating Synthetic Ligands for the Treatment of NASH

 描述（由申请人提供）：与蛋白质、碳水化合物和脂质异常加工相关的代谢性疾病是导致严重发病率和死亡率的原因。核受体，肝X受体α和β（LXR α和LXR β），最初被鉴定为核受体（NR）超家族的孤儿成员，其与类维生素A X受体（RXR）起异二聚体的作用。LXR α和LXR β两者在胆固醇生理学和脂质代谢中起重要作用，并且已经涉及几种疾病的病理学，包括动脉粥样硬化、癌症和肥胖症。对LXR α缺陷小鼠的详细检查揭示了大量关于其在调节代谢途径（包括脂质代谢）中的作用的信息。已经使用合成激动剂确定了LXR在代谢中的潜在药理学作用，但是我们这项研究的重点是使用反向激动剂治疗脂肪肝疾病。我们已经确定了一 新型合成LXR反向激动剂，其显示特异性抑制LXR靶基因表达的能力，特异性抑制肝脏中的LXR靶基因表达，因此具有抑制脂肪性肝炎的潜力。长期目标是使用这些化合物作为工具来研究合成LXR配体对肝脏疾病的影响。我们假设LXR反向激动剂可以抑制小鼠模型中脂肪肝疾病的影响。我们的假设将在以下特定目的中进行检验：特定目的1将检查SR9238影响LXR介导的脂肪生成、炎症和胆固醇调节的机制;特定目的2将评价SR9238作为非酒精性脂肪性肝炎（NASH）小鼠模型治疗药物的潜力。配体调节的核激素受体已被明确证明是药物开发的有效靶点。我们预测，这些研究将为靶向LXR治疗脂肪肝疾病和潜在的其他代谢紊乱的新疗法提供基础。

 DESCRIPTION (provided by applicant): Metabolic diseases, associated with abnormal processing of proteins, carbohydrates, and lipids, are the cause of significant morbidity and mortality. The nuclear receptors, liver X receptor a, and -ß (LXRa and LXRß), were originally identified as orphan members of the nuclear receptor (NR) superfamily that function as heterodimers with the retinoid X receptor (RXR). Both LXRa and LXRß play important roles in cholesterol physiology and lipid metabolism, and have been implicated in the pathology of several diseases, including athereosclerosis, cancer, and obesity. Detailed examination of mice deficient in LXRa have revealed a significant amount of information regarding its role in regulating metabolic pathways, including lipid metabolism. Potential pharmacological roles of LXR in metabolism have been identified using synthetic agonists, however our focus for this study is the use of inverse agonists in the treatment of fatty liver diseases. We have identified a novel synthetic LXR inverse agonist that displays the ability to specifically suppress LXR target gene expression specifically in the liver, thus having the potential to suppress steatohepatitis. The long-term objective is to use these compounds as tools to study the effects of synthetic LXR ligands on diseases of the liver. We hypothesize that LXR inverse agonists can suppress the effects Fatty Liver Diseases in mouse models. Our hypothesis will be tested in the following specific aims: Specific Aim 1 will examine the mechanism(s) by which SR9238 effects LXR-mediated lipogenesis, inflammation, and cholesterol regulation; Specific Aim 2 will evaluate the potential for SR9238 as a therapeutic in Non- Alcoholic Steatohepatitis (NASH) in mouse models of the disease. Ligand-regulated nuclear hormone receptors have been definitively shown to be effective targets for the development of pharmaceuticals. We predict that these studies will provide the basis for novel therapeutics targeting LXR for the treatment of fatty live diseases and potentially other metabolic disorders.