PPARα/γ agonists and antagonists differently affect hepatic lipid metabolism, oxidative stress and inflammatory cytokine production in steatohepatitic rats
PPARα/γ agonists and antagonists differently affect hepatic lipid metabolism, oxidative stress and inflammatory cytokine production in steatohepatitic rats
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DOI：
10.1016/j.cyto.2015.05.031
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发表时间：
2015-09-01
期刊：
影响因子：
3.8
通讯作者：
Xie, Mei-Lin
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Cui, Yan;Xie, Mei-Lin
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPAR）α/γ通过调节下游靶基因调控脂质代谢和炎症反应，在非酒精性脂肪性肝炎（non-alcoholic steatohepatitis，NASH）的形成过程中发挥重要作用，但其差异及相互作用尚不清楚。采用高脂高糖乳剂灌胃6周建立NASH大鼠模型。结果显示，模型大鼠同时给予PPAR α/γ激动剂治疗后，血清和肝组织中总胆固醇（TC）、甘油三酯（TG）和炎性细胞因子水平降低，肝脂肪变性和炎性细胞浸润减少，与肝脏脂肪生成基因和核因子（NF）-κ B蛋白表达结果一致。相反，这些指数增加了PPAR α/γ拮抗剂治疗。与模型组相比，PPARalpha激动剂治疗组血清游离脂肪酸（FFA）水平升高，PPARgamma激动剂治疗组血清游离脂肪酸（FFA）水平降低，PPARalpha/gamma激动剂治疗组血清游离脂肪酸（FFA）水平无变化。肝脏FFA水平在PPAR α/γ激动剂治疗组中较低，但在PPAR α/γ拮抗剂治疗组中无显著变化。肝脏还原型谷胱甘肽（GSH）和超氧化物歧化酶（SOD）含量的增加，在PPAR α/γ激动剂治疗组伴随着降低肝脏丙二醛（MDA）含量。这些结果表明，PPAR α/γ激活可能会减少肝脏脂质积聚，氧化应激和炎症细胞因子的产生，和PPAR γ可以抵消的不利影响，PPAR α对循环FFA。结论：PPARalpha和PPARgamma激动剂的联合应用可能通过调节PPARalpha/gamma介导的脂肪生成和炎症基因表达，对NASH的形成产生协同抑制作用。(C)2015爱思唯尔有限公司版权所有。
Peroxisome proliferator-activated receptor (PPAR) alpha/gamma may control lipid metabolism and inflammatory response by regulating the downstream target genes, and play a crucial role in the process of non-alcoholic steatohepatitis (NASH) formation, but the difference and interaction between PPAR alpha and PPAR gamma are poorly understood. The rat model with NASH was established by orally feeding high-fat and high-sucrose emulsion for 6 weeks. The results shown that after the model rats were simultaneously treated with PPAR alpha/gamma agonists, the total cholesterol (TC), triglyceride (TG) and inflammatory cytokine levels in serum and hepatic tissue, the hepatic steatosis and inflammatory cellular infiltration were decreased, and were consistent with the results of hepatic lipogenic gene and nuclear factor (NF)-kappa B protein expressions. Conversely, these indexes were increased by PPAR alpha/gamma antagonist treatment. Compared with the model group, the serum free fatty acid (FFA) level was increased in the PPAR alpha agonist-treated group, decreased in the PPAR gamma agonist-treated group, and unchanged in the PPAR alpha/gamma agonists-treated group. The hepatic FFA level was low in the PPAR alpha/gamma agonists-treated groups, but no significant variation in the PPAR alpha/gamma antagonists-treated groups. The increments of hepatic reduced glutathione (GSH) and superoxide dismutase (SOD) contents in the PPAR alpha/gamma agonists-treated groups were accompanied by decreased hepatic malondialdehyde (MDA) content. These findings demonstrated that PPAR alpha/gamma activation might decrease the hepatic lipid accumulation, oxidative stress and inflammatory cytokine production, and PPAR gamma could counterbalance the adverse effect of PPAR alpha on circulating FFA. It was concluded that the integrative application of PPAR alpha and PPAR gamma agonists might exert a synergic inhibitory effect on NASH formation through the modulation of PPAR alpha/gamma-mediated lipogenic and inflammatory gene expressions. (C) 2015 Elsevier Ltd. All rights reserved.