Morin reduces hepatic inflammation-associated lipid accumulation in high fructose-fed rats via inhibiting sphingosine kinase 1/sphingosine 1-phosphate signaling pathway
Morin reduces hepatic inflammation-associated lipid accumulation in high fructose-fed rats via inhibiting sphingosine kinase 1/sphingosine 1-phosphate signaling pathway
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DOI：
10.1016/j.bcp.2013.10.005
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发表时间：
2013-12-15
影响因子：
5.8
通讯作者：
Kong, Ling-Dong
中科院分区：
文献类型：
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作者：
Wang, Xing;Zhang, Dong-Mei;Kong, Ling-Dong
SphK 1/S1 P信号通路参与肝脏炎症和损伤的发生发展。但其在高果糖诱导的NAFLD中的作用尚未见报道。本研究的目的是阐明SphK 1/S1 P信号通路在高果糖诱导的大鼠肝脏炎症和脂质蓄积中的重要作用。此外，桑色素，黄酮类化合物与降血脂和抗高脂血症的活动，对这些肝脏变化的保护作用进行了研究。高果糖喂养的大鼠分别口服桑色素（30和60 mg/kg）和吡格列酮（4 mg/kg）8周。果糖喂养诱导大鼠高脂血症，激活SphK 1/S1 P信号通路，其特征在于SphK 1活性、SIP产生以及SphK 1、S1 PR 1和S1 PR 3蛋白水平升高，进而导致NF-κ B信号通路激活，产生IL-1 β、IL-6和TNF-α，并在大鼠肝脏中引起炎症。随后，在该动物模型中观察到肝脏胰岛素和瘦素信号传导障碍和脂质代谢紊乱，导致肝脏脂质蓄积。桑色素恢复高果糖诱导的大鼠肝脏SphK 1/S1 P信号通路的激活。随后，桑色素减少NF-κ B信号激活减少炎症细胞因子的产生，恢复胰岛素和瘦素信号损伤，以减少大鼠肝脏中的脂质积累和损伤。桑色素的这些作用在用5 mM果糖刺激的布法罗大鼠肝（BRL 3A）细胞模型中得到证实。因此，抑制肝脏SphK 1/S1 P信号通路可能是桑色素在高果糖喂养大鼠中发挥肝脏保护作用的一种新机制，可能涉及肝脏炎症抑制和脂质积累恢复。(C)2013 Elsevier Inc. All rights reserved.
SphK1/S1P signaling pathway is involved in the development of hepatic inflammation and injury. But its role in high fructose-induced NAFLD has not yet been reported. The aim of this study was to elucidate the crucial role of SphK1/S1P signaling pathway in high fructose-induced hepatic inflammation and lipid accumulation in rats. Moreover, the hepatoprotective effects of morin, a flavonoid with antiinflammatory and anti-hyperlipedimic activities, on these hepatic changes in rats were investigated. High fructose-fed rats were orally treated with morin (30 and 60 mg/kg) and pioglitazone (4 mg/kg) for 8 weeks, respectively. Fructose feeding induced hyperlipidemia, and activated SphK1/S1P signaling pathway characterized by the elevation of SphK1 activity, SIP production as well as SphK1, S1PR1 and S1PR3 protein levels, which in turn caused NF-kappa B signaling activation to produce IL-1 beta, IL-6 and TNF-alpha and inflammation in the liver of rats. Subsequently, hepatic insulin and leptin signaling impairment and lipid metabolic disorder were observed in this animal model, resulting in liver lipid accumulation. Morin restored high fructose-induced the activation of hepatic SphK1/S1P signaling pathway in rats. Subsequently, the reduced NF-kappa B signaling activation by morin decreased inflammatory cytokine production, recovered insulin and leptin signaling impairment to reduce lipid accumulation and injury in the rat liver. These effects of morin were confirmed in Buffalo rat liver (BRL3A) cell model stimulated with 5 mM fructose. Thus, the inhibition of hepatic SphK1/S1P signaling pathway may be a novel mechanism by which morin exerts hepatoprotection in high fructose-fed rats, possibly involving liver inflammation inhibition and lipid accumulation recovery. (C) 2013 Elsevier Inc. All rights reserved.