Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):117-23. doi: 10.1016/j.bbrc.2014.05.072. Epub 2014 May 27.
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 TNFα concentration. In lipopolysaccharide (LPS)-induced NAFLD model, WAY attenuated serum TNFα 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 TNFα-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.
果糖是导致非酒精性脂肪性肝病（NAFLD）的主要饮食因素。在此，我们研究了强效合成的、口服有效的法尼醇 X 受体（FXR）激动剂 WAY-362450（WAY）是否可预防果糖诱导的脂肪变性及其潜在机制。C57BL/6J 小鼠喂食 30%果糖 8 周，同时用或不用 WAY（30mg/kg）处理 20 天。喂食 30%果糖的小鼠血清和肝甘油三酯升高，经 WAY 处理后得到逆转。组织学上，WAY 显著减少肝内甘油三酯堆积，减弱巨噬细胞浸润并保护肠的连接完整性。此外，WAY 明显降低门静脉内毒素水平，并降低血清 TNFα 浓度。在脂多糖（LPS）诱导的 NAFLD 模型中，WAY 降低了血清 TNFα 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，其表达下调。此外，WAY 以剂量依赖的方式抑制棕榈酸（PA）处理的 HepG2 和 Huh7 细胞中的脂肪堆积和 ADRP 表达。WAY 通过与 AP-1 竞争 ADRP 启动子结合区域，抑制 TNFα 诱导的 ADRP 上调。综上，我们的研究结果表明，FXR 激动剂 WAY 通过多种机制减轻肝脂肪变性，这些机制在肝脂肪变性的发生中起关键作用，为 NAFLD 的治疗提供了一种候选药物。
