Genistein Ameliorates Non-alcoholic Fatty Liver Disease by Targeting the Thromboxane A(2) Pathway
Genistein Ameliorates Non-alcoholic Fatty Liver Disease by Targeting the Thromboxane A(2) Pathway
复制标题
金雀异黄素通过靶向血栓素 A(2) 途径改善非酒精性脂肪肝
DOI：
10.1021/acsjafc.8b01691
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发表时间：
2018
影响因子：
6.1
通讯作者：
Chen Wei
中科院分区：
文献类型：
--
作者：
Wang Wenzhe;Chen Junliang;Mao Jinyan;Li Hongling;Wang Mingfu;Zhang Hao;Li Haitao;Chen Wei
非酒精性脂肪性肝病（NAFLD）现在是一个全球性的公共卫生问题，但还没有药物获得批准。染料木黄酮是一种来源于大豆的黄酮类化合物，可以改善高脂饮食诱导的小鼠NAFLD，但其分子基础仍然很难确定。花生四烯酸（AA）是动物脂肪的主要成分，AA级联反应与慢性炎症有关。在这项研究中，我们研究了染料木黄酮是否通过靶向AA级联反应来对抗NAFLD。使用小鼠模型，我们发现染料木黄酮补充剂通过使肝肿大、肝脂肪变性、转氨酶异常和葡萄糖耐量正常化来改善高脂饮食诱导的NAFLD。血栓素A2（TXA 2）通路在NAFLD中异常活跃，表现为循环TXA 2和肝脏血栓素A2受体表达升高。机制上，我们发现染料木黄酮直接靶向环氧合酶-1活性及其下游TXA 2的生物合成，而TXA 2途径可能通过损害胰岛素敏感性介导NAFLD的进展。综上所述，我们的研究揭示了TXA 2通路在NAFLD中的重要病理生理作用，并解释了染料木黄酮是如何对抗NAFLD进展的。
Non-alcoholic fatty liver disease (NAFLD) is now a public health issue worldwide, but no drug has yet received approval. Genistein, an isoflavonoid derived from soybean, ameliorates high-fat-diet-induced NAFLD in mice, but the molecular underpinnings remain largely elusive. Arachidonic acid (AA) is a major ingredient of animal fats, and the AA cascade has been implicated in chronic inflammation. In this study, we investigated whether genistein was against NAFLD by targeting the AA cascade. Using a mouse model, we showed that genistein supplementation improved high-fat-diet-induced NAFLD by normalizing hepatomegaly, liver steatosis, aminotransferase abnormalities, and glucose tolerance. The thromboxane A2(TXA2) pathway was aberrantly active in NAFLD, evidenced by an elevation of circulating TXA2and hepatic thromboxane A2receptor expression. Mechanistically, we found that genistein directly targeted cyclooxygenase-1 activity as well as its downstream TXA2biosynthesis, while the TXA2pathway might mediate NAFLD progression by impairing insulin sensitivity. Taken together, our study revealed a crucial pathophysiological role of the TXA2pathway in NAFLD and provided an explanation as to how genistein was against NAFLD progression.