Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction
Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction
复制标题
法尼醇 X 受体 (FXR) 的激活可通过抑制炎症和减少 ADRP 来防止果糖诱导的肝脏脂肪变性。
DOI：
10.1016/j.bbrc.2014.05.072
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发表时间：
2014-07-18
影响因子：
3.1
通讯作者：
Chen, She
中科院分区：
文献类型：
--
作者：
Liu, Xijun;Xue, Ruyi;Chen, She
果糖是非酒精性脂肪性肝病（NAFLD）发展的关键饮食因素。在这里，我们研究了WAY-362450（WAY），一种有效的合成和口服活性FXR激动剂，是否可以预防果糖诱导的脂肪变性及其潜在机制。喂食30%果糖8周的C57 BL/6 J小鼠用或不用WAY（30 mg/kg）处理20天。WAY处理可逆转喂食30%果糖的小鼠血清和肝脏甘油三酯的升高。在组织学上，WAY显著减少肝脏中甘油三酯的积累，减弱微噬细胞浸润，并保护肠连接的完整性。WAY还能显著降低门脉内毒素水平和血清TNF α浓度。在脂多糖（LPS）诱导的NAFLD模型中，WAY降低血清TNF α水平。此外，WAY抑制LPS诱导的肝脂滴蛋白脂肪分化相关蛋白（ADRP）的表达，在喂食30%果糖的小鼠中下调。此外，WAY抑制脂质积累和ADRP的表达在棕榈酸（PA）处理的HepG 2和Huh 7细胞以剂量依赖性的方式。WAY通过与AP-1竞争ADRP启动子结合区抑制TNF α诱导的ADRP上调。总之，我们的研究结果表明，WAY，一种FXR激动剂，通过与脂肪肝发展密切相关的多种机制来减轻肝脏脂肪变性，并代表了NAFLD治疗的候选药物。(C)2014爱思唯尔公司All rights reserved.
Fructose is a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). Here we investigated whether WAY-362450 (WAY), a potent synthetic and orally active FXR agonist, protects against fructose-induced steatosis and the underlying mechanisms. C57BL/6J mice, fed 30% fructose for 8 weeks, were treated with or without WAY, 30 mg/kg, for 20 days. The elevation of serum and hepatic triglyceride in mice fed 30% fructose was reversed by WAY treatment. Histologically, WAY significantly reduced triglyceride accumulation in liver, attenuated microphage infiltration and protected the junction integrity in intestine. Moreover, WAY remarkably decreased portal endotoxin level, and lowered serum TNF alpha concentration. In lipopolysaccharide (LPS)-induced NAFLD model, WAY attenuated serum TNF alpha level. Moreover, WAY suppressed LPS-induced expression of hepatic lipid droplet protein adipose differentiation-related protein (ADRP), down-regulation of it in mice fed 30% fructose. Furthermore, WAY repressed lipid accumulation and ADRP expression in a dose-dependent manner in palmitic acid (PA)-treated HepG2 and Huh7 cells. WAY suppressed TNF alpha-induced ADRP up-regulation via competing with AP-1 for ADRP promoter binding region. Together, our findings suggest that WAY, an FXR agonist, attenuates liver steatosis through multiple mechanisms critically involved in the development of hepatosteatosis, and represents a candidate for NAFLD treatment. (C) 2014 Elsevier Inc. All rights reserved.