Weiyi Zhang1, Jie Gao2, Fukui Shen1, Xiaoyao Ma1, Zhihua Wang1, Xiaotao Hou3, Erwei Hao3, Yuanyuan Hou4, Gang Bai5. 1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China. 2. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China. Electronic address: gaojie@nankai.edu.cn. 3. Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China. 4. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China. Electronic address: houyy@nankai.edu.cn. 5. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China. Electronic address: gangbai@nankai.edu.cn.
Abstract
AIMS: Hepatic glucose metabolism involves a variety of catabolic and anabolic pathways, and the dynamic balance of glucose metabolism is regulated in response to environmental and nutritional changes. The molecular mechanism of glucose metabolism in liver is complex and has not been fully elucidated so far. In this study, we hope to elucidate the target and mechanism of cinnamaldehyde (CA) in regulating glucose metabolism. MATERIALS AND METHODS: Molecular image tracing and magnetic capture in combination with an alkynyl-CA probe (Al-CA) was used to show CA covalently binds to α-enolase (ENO1) in both mouse liver and HepG2 cells. Accurate metabolic flow assays subsequently demonstrated that the utilization of glycogenic amino acids and the biosynthesis of tricarboxylic acid (TCA) cycle intermediates were strengthened, which was detected using nontargeted and targeted metabolomics analyses. KEY FINDINGS: Our study shows that CA covalently bonds with ENO1, which affects the stability and activity of ENO1 and changes the dynamic balance of glucose metabolism. The interruption of gluconeogenic reflux by ENO1 enhanced TCA cycle, and eventually led to a decrease in blood glucose and the improvement of mitochondrial efficiency. SIGNIFICANCE: These results provide a detailed description of how CA maintains the dynamic balance of glucose utilization and improves energy metabolism.
AIMS: Hepatic glucose metabolism involves a variety of catabolic and anabolic pathways, and the dynamic balance of glucose metabolism is regulated in response to environmental and nutritional changes. The molecular mechanism of glucose metabolism in liver is complex and has not been fully elucidated so far. In this study, we hope to elucidate the target and mechanism of cinnamaldehyde (CA) in regulating glucose metabolism. MATERIALS AND METHODS: Molecular image tracing and magnetic capture in combination with an alkynyl-CA probe (Al-CA) was used to show CA covalently binds to α-enolase (ENO1) in both mouse liver and HepG2 cells. Accurate metabolic flow assays subsequently demonstrated that the utilization of glycogenic amino acids and the biosynthesis of tricarboxylic acid (TCA) cycle intermediates were strengthened, which was detected using nontargeted and targeted metabolomics analyses. KEY FINDINGS: Our study shows that CA covalently bonds with ENO1, which affects the stability and activity of ENO1 and changes the dynamic balance of glucose metabolism. The interruption of gluconeogenic reflux by ENO1 enhanced TCA cycle, and eventually led to a decrease in blood glucose and the improvement of mitochondrial efficiency. SIGNIFICANCE: These results provide a detailed description of how CA maintains the dynamic balance of glucose utilization and improves energy metabolism.