A Liver-Selective LXR Inverse Agonist That Suppresses Hepatic Steatosis
A Liver-Selective LXR Inverse Agonist That Suppresses Hepatic Steatosis
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DOI：
10.1021/cb300541g
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发表时间：
2013-03-01
影响因子：
4
通讯作者：
Burris, Thomas P.
中科院分区：
文献类型：
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作者：
Griffett, Kristine;Solt, Laura A.;Burris, Thomas P.
脂肪肝通常伴随着肥胖和2型糖尿病，通常会导致更严重的肝病，包括非酒精性脂肪性肝炎、肝硬变和肝细胞癌。目前的药物治疗缺乏确凿的疗效，因此治疗选择有限，抑制肝脏脂肪生成和/或肝脏炎症的新疗法可能是有用的。在这里，我们描述了第一个选择性合成的LXR反向激动剂(SR9238)的开发，并证明了该化合物有效地抑制了非酒精性肝骨病小鼠模型的肝脏脂肪生成、炎症和肝脏脂肪堆积。SR9238表现出对LXRα和LXRβ(40-200 NM IC50)的高效力，并被设计为显示肝脏特异性，以避免由于抑制LXR而在外围产生的潜在副作用。出乎意料的是，SR9238对饮食诱导的肥胖小鼠的治疗降低了血浆胆固醇水平。这些数据表明，肝脏选择性LXR反向激动剂可能在肝脏疾病的治疗中具有实用价值。
Fatty liver, which often accompanies obesity and type 2 diabetes, frequently leads to a much more debilitating hepatic disease including non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Current pharmacological therapies lack conclusive efficacy and thus treatment options are limited Novel therapeutics that suppress either hepatic lipogenesis and/or hepatic inflammation may be useful. Here, we describe the development of the first selective synthetic LXR inverse agonist (SR9238) and demonstrate that this compound effectively suppresses hepatic lipogenesis, inflammation, and hepatic lipid accumulation in a mouse model of non-alcoholic hepatosteatosis. SR9238 displays high potency for both LXR alpha and LXR beta (40-200 nM IC50) and was designed to display liver specificity so as to avoid potential side effects due to suppression of LXR in the periphery. Unexpectedly, treatment of diet-induced obese mice with SR9238 suppressed plasma cholesterol levels. These data indicate that liver-selective LXR inverse agonists may hold utility in the treatment of liver disease.