Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 26; pp. E5896 - E5905
• Main Authors: Dai, Jianye, Liang, Kai, Zhao, Shan, Jia, Wentong, Liu, Yuan, Wu, Hongkun, Lv, Jia, Cao, Chen, Chen, Tao, Zhuang, Shentian, Hou, Xiaomeng, Zhou, Shijie, Zhang, Xiannian, Chen, Xiao-Wei, 陈晓伟, Huang, Yanyi, Xiao, Rui-Ping, Wang, Yan-Ling, Luo, Tuoping, Xiao, Junyu, Wang, Chu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.06.2018
• Series: PNAS Plus
• Subjects: Allosteric properties; Allosteric Regulation - drug effects; Animals; Baicalin; Binding Sites; Biological Sciences; Carnitine; Carnitine O-Palmitoyltransferase - metabolism; Carnitine palmitoyltransferase; Complications; Diet; Diet - adverse effects; Drug therapy; Enzyme Activation - drug effects; Epidemics; Fatty liver; Fatty Liver - chemically induced; Fatty Liver - enzymology; Fatty Liver - pathology; Fatty Liver - prevention & control; Flavonoids; Flavonoids - pharmacology; HeLa Cells; Herbal medicine; Humans; Liver; Liver - enzymology; Liver - pathology; Liver diseases; Medical treatment; Metabolic disorders; Mice; Mitochondria; Mitochondria, Liver - enzymology; Mitochondria, Liver - pathology; Obesity; Obesity - chemically induced; Obesity - enzymology; Obesity - prevention & control; Oxidation; Palmitoyltransferase; Pharmacology; Physical Sciences; PNAS Plus; Proteomics; Steatosis; chemical proteomics; baicalin; CPT1; steatosis; obesity
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1801745115

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.