Oleanolic acid derivative HA-20 inhibits adipogenesis in a manner involving PPARγ-FABP4/aP2 pathway
Oleanolic acid derivative HA-20 inhibits adipogenesis in a manner involving PPARγ-FABP4/aP2 pathway
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DOI：
10.1530/jme-20-0075
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发表时间：
2021-03-01
影响因子：
3.5
通讯作者：
Li, Jian-Xin
中科院分区：
文献类型：
--
作者：
Wang, Jie;Zhang, Yuchao;Li, Jian-Xin
肥胖是一种慢性疾病，会增加II型糖尿病、心脏病和非酒精性脂肪肝的风险。不幸的是，迄今为止，只有少数药物被批准用于临床。本研究旨在发现基于天然来源的油酸（OA）衍生物的抗肥胖剂。体外诱导3 T3-L1前脂肪细胞分化为成熟脂肪细胞，并建立高脂饮食诱导的肥胖小鼠模型进行体内研究。用3 T3-L1细胞进行OA衍生物的筛选，发现了对3 T3-L1脂肪生成具有有效抑制活性的新化合物HA-20。体外实验结果表明，HA-20对3 T3-L1细胞早期成脂有明显的抑制作用，且无细胞毒性。使用HFD小鼠的体内研究显示，HA-20降低了体重，并具有降脂作用。转录组分析发现，HA-20调控的脂肪生成基因主要为Pparg、Cebpa、Fas、Acc和Fabp 4/aP 2。机制研究表明，HA-20至少通过下调3 T3-L1中的PPAR γ-FABP 4/aP 2通路发挥其生物活性作用，这一点在HFD诱导的肥胖小鼠中得到进一步证实。我们的研究结果为基于OA衍生物的抗脂肪积聚提供了新的见解，并表明HA-20可能成为进一步开发抗肥胖剂的有价值的先导化合物。
Obesity is a chronic disease that increases the risk of type II diabetes, heart diseases and nonalcoholic fatty liver disease. Unfortunately, to date, only a handful of drugs are approved for clinical use. This study aims at the discovery of anti-obesity agents based on naturally sourced oleanolic acid (OA) derivatives. 3T3-L1 preadipocytes were differentiated into mature adipocytes for in vitro assays, and a high-fat diet (HFD)induced obesity mice model was established for in vivo studies. The screening of the OA derivatives was performed with 3T3-L1 cell, and resulted in a discovery of a novel compound HA-20 with a potent inhibitory activity on 3T3-L1 adipogenesis. In vitro data demonstrated that HA-20 markedly suppressed the adipogenesis in 3T3-L1 at the early stage without cytotoxicity. In vivo research using HFD mice revealed that HA-20 lowered the body weight, and possessed a lipid-lowering effect. Transcriptome analysis discovered that the mainly adipogenesis/lipogenesis genes regulated by HA-20 were Pparg, Cebpa, Fas, Acc, and Fabp4/aP2. Mechanism study revealed that HA-20 played its bioactive roles at least via downregulating PPAR gamma-FABP4/aP2 pathway in 3T3-L1, which was further confirmed in HFD-induced obesity mice. Our findings provided a new insight into fighting fat accumulation based on OA derivatives, and demonstrated that HA-20 may sever as a worthy leading compound for the further development of anti-obesity agents.