RESUMEN
Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.
RESUMEN
Objective To investigate the pharmacological components of "Szechwan Chinaberry Fruit-Rhizoma Corydalis" drug combination and its potential molecular mechanism in the treatment of liver cancer based on network pharmacology. Methods Related databases, such as TCMSP, Uniprot, and GeneCard, were used to obtain the effective components of Szechwan Chinaberry Fruit and Rhizoma Corydalis, their corresponding action targets, and the disease targets of liver cancer, and the intersecting targets of drugs and diseases were selected. In addition, STRING and Metascape databases were used to screen out the core targets of drug action and perform GO function and KEGG pathway enrichment analyses. Results There were 9 active components in Szechwan Chinaberry Fruit and 49 active components in Rhizoma Corydalis, with 1 common component between the two drugs; there were 181 action targets of Szechwan Chinaberry Fruit and 1097 action targets of Rhizoma Corydalis, with 143 common targets between the two drugs. There were 162 intersecting targets between the drug combination and liver cancer, and the main genes involved were IL6, TP53, VEGFA, TNF, and CASP3. KEGG analysis showed that the main pathways involved included cancer pathway, AGE-RAGE signaling pathway of diabetes complications, TNF signaling pathway, NF-κB signaling pathway, and thyroid hormone signaling pathway. Conclusion There are many different components in the drug combination of "Szechwan Chinaberry Fruit-Rhizoma Corydalis", which can exert a therapeutic effect on liver cancer by acting on related genes and signaling pathways.