A study on the target and mechanism of jaundice lipid reduction effect

Introduction: With our country's attention to Chinese medicine and its natural product molecules in various diseases, around the target and functional research of natural molecules will once again become a hot spot in drug research and development
with the development of society, obesity has become one of the major health problems facing contemporary peopleObesity is mainly characterized by excess lipids, which in turn cause a series of cardiovascular, digestive and even respiratory diseasesMitochondria's fatty acid beta-oxidation (fattyacid beta-oxidation, FAO) is the main route of lipid consumption, the key step is to transfer the fatty acid coenzyme A to the mitochondria and produce acetyl coenzyme AIn the process, the carnitinepalmitoyltransferase (CPT) system, especially the CPT1 protein, is FAO's speed limit enzymeTherefore, improving the activity of CPT1A is the key to promote fatty acid metabolismstudies have shown that many natural flavonoids with reduced fat activity have ato promote the transcription of CPT1However, it is still unclear whether these natural products directly excite the activity of CPT1jaundiceis a lip-shaped plant, rich in flavonoids, its coarse lifting has a strong fat-lowering effectthe plant's main component, jadeside, can significantly reduce the dietary-induced liver fat degeneration, but its mechanism is still unclearbased on this, The Wang Chu team of Peking University, with jaundice as the research object,through chemical proteomics and molecular biology research, identified the main target of jaundice sein reduction CPT1A and its mechanism of actionfirst, the researchers studied the in vitro lipid reduction activity and cytotoxicity of jaundice, and found that jaundice can play a lipid-lowering effect at 12.5 m, and its cytotoxicity is relatively low, confirming the results reported in the previous literatureBecause there is no obvious "covalent group" in the structure of jaundice, in order to further explore the possible role of jaundice, the researchers first modified the structure of jadesinin, successfully introduced a photosynthesis group bioorthortoogonal group to it, and constructed the probe molecule BP and its control molecular CPThe researchers then used SILAC-ABPP to determine the protein expression differences in the competitive binding of BP probes and jaundice Because the introduction of optical crosslinking probes may produce more nonspecific binding, the researchers also set up three control groups (BPcontrol, UVcontrol, and CPcontrol) with different treatment conditions Through a joint analysis of the differential proteins of three control groups and competitive experimental groups, the researchers identified 142 proteins with potential for further research The Gene Ontology analysis showed that the 142 proteins were highly correlated with fatty acid metabolic pathways, which were consistent with phenotypes of jaundice in lipid reduction activity Further analysis shows that the pathway involves seven proteins, ALDH3A2, ACSL1, ACSL3, ACSL4, CPT1A, ACADVL and HADHA By knocking out the seven proteins one by one, the researchers found that when CPT1A was knocked out, the activity of jaundice was completely lost, suggesting that CPT1A may be the main target of jaundice later, the researchers confirmed, through biophysical and molecular biology methods, that jaundice can be directly combined with CPT1A and can be excited in the activity of CPT1A in complete cell, cell lysis and mitochondrial extracts, without affecting the activity of CPT1B and CPT1C Through RD-ABPP analysis and molecular docking simulation, the author obtained four key amino acids with jaundice, and through mutation experiments, it was confirmed that the four amino acids are the key amino acids that affect the binding of jaundice and CPT1A further, the researchers validated the invivia-reducing activity of jaundice in the body using a diet-induced obesity (diet-induced induced obesity, DIO) mouse model: jaundice reduced the weight and reduced the body fat ratio of DIO mice at a concentration of 400 mg/kg Without affecting the amount of mice eating, promote energy exchange, reduce their respiratory exchange ratio, improve liver lipid aggregation and liver weight, reduce the content of liver cholesterol and triglycerides, and confirm that the invivirate reduction effect of jaundice is effective through CPT1A , jaundice can be "opened" by CPT1A, allowing more fat to enter mitochondria combustion, and thus play a role in reducing fat With our country's attention to Chinese medicine and its natural product molecules in various diseases, the research on the target and function of natural molecules will become a hot spot in drug research and development again references
Dai, J.; Liang, K.; Zhao, S.; Jia, W.; Liu, Y.; Wu, H.; Lv, J.; Cao, C.; Chen, T.; Zhuang, S.; Hou, X.; Zhou, S.; Zhang, X.; Chen, X W.; Huang, Y.; Xiao, R P.; Wang, Y L.; Luo, T.; Xiao, J.; Wang, C Chemoproteomics Reveals Baicalin Activates Hepatic CPT1 to Ameliorate Diet-Induced Obesity and Hepatic Steatosis Proc Natl Acad Sci U S A 2018, 115, E5896-E5905