番荔枝内酯类似物AA005靶向HADHA抑制肥胖及其分子机制研究

Obesity and related disease is a serious threat to people's health problems. However, currently available anti-obesity drugs are few and the side effects are obvious, it is necessary to explore more safe and effective new compounds. Recently, we found annonaceous acetogenin mimic AA005 treatment could inhibit the fat accumulation in preadipocyte 3T3-L1 cells and resist obesity in diet-induced obese (DIO) mice and leptin-deficient (ob/ob) mice at non-toxic dose. In order to find its targets, we synthesized the biotin labeled AA005 (biotin-AA005), and 35 proteins were captured as AA005 interaction proteins using chemical proteomics. After RNAi screening of these proteins, alpha subunit of mitochondrial trifunctional protein (HADHA) was found to suppress the fat accumulation in 3T3-L1 cells similar to AA005, suggesting that HADHA may be its target. Based on these original findings, in this project we will continue to confirm the interaction between AA005 and HADHA and mechanisms underlying its inhibition of obesity. Collectively, all these work would shed new sight for understanding the novel function of AA005, provide new active compounds and novel therapeutic clues for treating obesity.

肥胖及其相关疾病对当今人口健康构成严重威胁，然而目前可用的抗肥胖药物很少，且副作用明显，亟需发掘更多安全有效的新型化合物。最近，本课题组发现无细胞毒性的番荔枝内酯类似物AA005能够明显抑制前脂肪细胞3T3-L1中脂肪的累积，以及高脂饮食小鼠和瘦素缺失小鼠的肥胖。为了发现其药物靶点，我们构建了生物素标记的AA005（biotin-AA005），利用化学蛋白质组学方法钓取到与化合物AA005结合的蛋白质35种；并利用RNAi技术进一步筛选这些蛋白质，从中发现线粒体三功能酶alpha亚基（HADHA）在沉默表达后导致3T3-L1细胞中的脂肪累积显著减少，提示AA005的潜在靶点为HADHA。本课题拟以这些研究结果为基础，进一步深入研究AA005与HADHA之间的相互作用，解析化合物AA005抗肥胖的药物靶点和分子机制，为预防及治疗肥胖及其相关疾病提供新的活性化合物和药物靶点。

肥胖及其相关疾病对当今人口健康构成严重威胁，然而目前可用的抗肥胖药物很少，且副作用明显，亟需发掘更多安全有效的新型化合物。本研究发现无细胞毒性的番荔枝内酯类似物AA005有效治疗高脂饮食小鼠和瘦素缺失小鼠的肥胖；利用化学蛋白质组学方法结合RNAi技术，发现AA005的直接靶蛋白为线粒体三功能酶alpha亚基（HADHA）；药代动力学分析表明AA005主要分布在肝脏和脂肪组织，并且肝脏和脂肪组织特异性缺失HADHA的小鼠也能治疗高脂饮食小鼠的肥胖，在AA005处理和HADHA缺失小鼠中检测到能量消耗增加和产热途径激活；这些结果提示AA005通过靶向HADHA激活产热通路治疗肥胖。在本项目资助下，课题负责人作为通讯作者等，将本研究相关研究成果在Food Funct、Pathol Res Pract、Theranostics等杂志发表SCI论文12篇，同时，基于本研究进展，课题负责人获得上海市医学科技三等奖1项，申报及获得国家专利6项，顺利完成上海市青年科技英才扬帆计划1项，获得2020年度上海市闵行区优秀青年人才。本研究揭示了番荔枝内酯类似物AA005抗肥胖的药物靶点和分子机制，为临床获得预防及治疗肥胖的新型药物和治疗靶标提供了新线索。