The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis.
The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis.
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LXR反向激动剂SR9238在非酒精性脂肪性肝炎模型中抑制纤维化。
DOI：
10.1016/j.molmet.2015.01.009
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发表时间：
2015-04
影响因子：
8.1
通讯作者：
Burris TP
中科院分区：
文献类型：
--
作者：
Griffett K;Welch RD;Flaveny CA;Kolar GR;Neuschwander-Tetri BA;Burris TP
非酒精性脂肪性肝炎（NASH）的特征在于肝脂肪变性、炎症和纤维化。目前还没有针对NASH的靶向治疗。我们开发了一种肝脏特异性LXR反向激动剂SR9238，可有效降低肥胖和肝脂肪变性模型中的肝脏脂肪生成。我们假设，抑制脂肪生成（在NASH中病理性升高）可能会抑制肝脏脂肪变性向NASH的进展。在B6 V-lep ob/J（ob/ob）小鼠中使用含有大量反式脂肪、果糖和胆固醇的定制完全啮齿动物饮食（HTF）诱导NASH。一旦诱导NASH，通过腹膜内注射用SR9238处理小鼠一个月。通过临床化学分析血脂水平和肝脏健康状况。QPCR、蛋白质印迹和免疫组织化学用于评估疾病严重程度。Ob/ob小鼠是肥胖和糖尿病的，因此它们通常用作研究代谢疾病的模型。当提供HTF饮食时，这些小鼠迅速发展NASH表型。小鼠在HTF饮食中发生肝脂肪变性、严重的肝脏炎症和纤维化。SR9238治疗显著降低了肝脂肪变性的严重程度，最重要的是减少了肝脏炎症并改善了肝纤维化。在这里，我们证明了LXR反向激动剂SR9238在NASH动物模型中有效减少肝脂肪变性、炎症和纤维化。这些结果对人类NASH治疗方法的开发具有重要意义。
Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation and fibrosis. There are currently no targeted therapies for NASH. We developed a liver-specific LXR inverse agonist, SR9238, which effectively reduces hepatic lipogenesis in models of obesity and hepatic steatosis. We hypothesized that suppression of lipogenesis, which is pathologically elevated in NASH may suppress progression of hepatic steatosis to NASH. NASH was induced in B6 V-lep ob/J (ob/ob) mice using a custom complete rodent diet (HTF) containing high amounts of trans-fat, fructose, and cholesterol. Once NASH was induced, mice were treated with SR9238 for one month by i.p. injection. Plasma lipid levels and liver health were analyzed by clinical chemistry. QPCR, western blot, and immunohistochemistry were used to assess disease severity. Ob/ob mice are obese and diabetic thus they are commonly used as models for the study of metabolic diseases. These mice quickly developed the NASH phenotype when provided the HTF diet. The mice develop hepatic steatosis, severe hepatic inflammation and fibrosis on the HTF diet. Treatment with SR9238 significantly reduced the severity of hepatic steatosis and most importantly reduced hepatic inflammation and ameliorated hepatic fibrosis. Here, we demonstrate that an LXR inverse agonist, SR9238, is effective in reduction of hepatic steatosis, inflammation and fibrosis in an animal model of NASH. These results have important implications for the development of therapeutics for treatment NASH in humans.
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DOI：
10.1126/science.1168974
发表时间：
2009-07-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zelcer N;Hong C;Boyadjian R;Tontonoz P
通讯作者：
Tontonoz P
影响因子：
4.8
作者：
Sun, Y;Hao, MM;Tall, AR
通讯作者：
Tall, AR
影响因子：
15.9
作者：
Bradley, Michelle N.;Hong, Cynthia;Tontonoz, Peter
通讯作者：
Tontonoz, Peter
影响因子：
4.8
作者：
Tosello-Trampont, Annie-Carole;Landes, Susan G.;Hahn, Young S.
通讯作者：
Hahn, Young S.
DOI：
10.1111/j.1399-3011.2004.00126.x
发表时间：
2004-03-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Savkur, RS;Burris, TP
通讯作者：
Burris, TP