Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation
Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation
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芹菜素是 PPARγ 的调节剂，通过 Nrf2 激活调节肝细胞脂质代谢和氧化应激，从而减轻 HFD 诱导的 NAFLD
DOI：
10.1016/j.bcp.2017.04.014
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发表时间：
2017-07-15
影响因子：
5.8
通讯作者：
Shen, Pingping
中科院分区：
文献类型：
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作者：
Feng, Xiujing;Yu, Wen;Shen, Pingping
肝脏中的脂质代谢紊乱和氧化应激是非酒精性脂肪性肝病（NAFLD）进展的关键步骤，非酒精性脂肪性肝病是代谢综合征发展的主要危险因素。迄今为止，尚未批准用于这种疾病的药物治疗。我们以前的研究发现，食品来源的化合物芹菜素（API）显着减轻肥胖引起的代谢综合征作为过氧化物酶体增殖物激活受体γ调节剂（PPARM）。本研究采用高脂饮食（HFD）诱导的大鼠NAFLD模型，探讨API对NAFLD的治疗作用。结果表明，API具有明显的抑制NAFLD进展的作用，包括减轻HFD诱导的体内脂质蓄积和氧化应激。API作为PPARM，虽然能显著抑制与脂质代谢相关的蛋白质编码的PPAR γ靶基因的表达，但对PPAR γ没有明显的激活作用。有趣的是，我们发现API促进Nrf 2进入细胞核，从而显著激活Nrf 2，抑制脂质代谢相关基因，增加氧化应激相关基因。进一步的Nrf 2敲低/敲除和过表达实验表明，API调节PPAR γ靶基因依赖于Nrf 2激活，并且Nrf 2的激活抵消了API对PPAR γ的激活作用。重要的是，我们还发现API可以通过自动对接和ITC测定与Nrf 2结合。因此，我们的研究结果表明，API改善NAFLD通过一种新的调节模式，Nrf 2和PPAR γ抑制脂质代谢和氧化应激。(C)2017爱思唯尔公司All rights reserved.
Lipid metabolic disorders and oxidative stress in the liver are key steps in the progression of nonalcoholic fatty liver disease (NAFLD), which is a major risk factor for the development of metabolic syndrome. To date, no pharmacological treatment for this condition has been approved. Our previous study has found that the food-derived compound apigenin (Api) significantly attenuates obesity induced metabolic syndrome by acting as a peroxisome proliferator-activated receptor gamma modulator (PPARM). Herein, a high fat diet (HFD) induced NAFLD model was used to dig out whether Api had the effect on NAFLD. The results showed that Api had obvious effect in restraining NAFLD progression, including attenuating HFD induced lipid accumulation and oxidative stress in vivo. As a PPARM, although Api did significantly inhibit the expression of PPAR gamma target genes encoding the protein associated with lipid metabolism, it had no obvious activating effect on PPAR gamma. Interestingly, we found that Api promoted Nrf2 into the nucleus, thereby markedly activating Nrf2 to inhibit the lipid metabolism related genes and increase the oxidative stress related genes. Further Nrf2 knockdown/knockout and overexpression experiments showed that Api regulating PPAR gamma target genes was dependent on Nrf2 activation and the activation of Nrf2 counteracted the activation effect of PPAR gamma by Api. Importantly, we also found that Api might bind with Nrf2 via auto dock and ITC assay. Therefore, our results indicate that Api ameliorates NAFLD by a novel regulating mode of Nrf2 and PPAR gamma in inhibiting lipid metabolism and oxidative stress abnormity. (C) 2017 Elsevier Inc. All rights reserved.