Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis
Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis
复制标题
化学蛋白质组学揭示黄芩苷可激活肝脏 CPT1 以改善饮食引起的肥胖和肝脂肪变性。
DOI：
10.1073/pnas.1801745115
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发表时间：
2018-06-26
影响因子：
11.1
通讯作者：
Wang, Chu
中科院分区：
文献类型：
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作者：
Dai, Jianye;Liang, Kai;Wang, Chu
肥胖症和相关的代谢性疾病正在成为世界性的流行病，导致死亡率增加和沉重的医疗保健费用。目前尚未找到有效的治疗方案。在这里，基于观察黄芩苷，黄酮类化合物从草药黄芩，具有独特的抗脂肪变性活性，我们进行了定量化学蛋白质组学分析，并确定肉毒碱棕榈酰转移酶1（CPT 1），脂肪酸氧化的控制酶，作为黄芩苷的关键目标。类黄酮直接激活肝CPT1亚型选择性，加速脂质流入线粒体氧化。黄芩苷的长期治疗改善了饮食诱导的肥胖（DIO）和肝脂肪变性，并导致其他代谢紊乱的全身改善。破坏黄芩苷对CPT 1的预测结合位点完全消除了黄酮类化合物的有益作用。我们发现黄芩苷是一种变构CPT 1激活剂，这为DIO及其相关后遗症的药物治疗提供了新的机会。
Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis, has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.