Dataset Information

Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPAR? and PPAR?.

ABSTRACT: UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPAR? and PPAR? in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPAR? and PPAR? in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPAR? and PPAR?. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPAR? and PPAR?. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.

SUBMITTER: Zhu YD

PROVIDER: S-EPMC7897654 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ.

Zhu Ya-Di YD Guan Xiao-Qing XQ Chen Jing J Peng Sheng S Finel Moshe M Zhao Ying-Yuan YY Wang Rui-Min RM Bi Hui-Chang HC Lei Ming M Wang Dan-Dan DD Ge Guang-Bo GB

Frontiers in pharmacology 20210208

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism ...[more]

PMID: 33628187

Similar Datasets

Project description:Lipid accumulation in macrophages interacts with microenvironment signals and accelerates diabetic atherosclerosis. However, the molecular mechanisms by which macrophage metabolism interacts with microenvironment signals during lipid accumulation are not clearly understood. Accordingly, an untargeted metabolomics approach was employed to characterize the metabolic reprogramming, and to identify potential regulatory targets related to lipid accumulation in macrophages treated with oleate, an important nutrient. The metabolomics approach revealed that multiple metabolic pathways were significantly disturbed in oleate-treated macrophages. We discovered that amino acids, nucleosides, lactate, monoacylglycerols, total free fatty acids (FFAs), and triglycerides (TGs) accumulated in oleate-treated macrophages, but these effects were effectively attenuated or even abolished by resveratrol. Notably, 1-monooleoylglycerol and 2-monooleoylglycerol showed the largest fold changes in the levels among the differential metabolites. Subsequently, we found that oleate triggered total FFA and TG accumulation in macrophages by accelerating FFA influx through the activation of Fatp1 expression, but this effect was attenuated by resveratrol via the activation of PPARα and PPARγ signaling. We verified that the activation of PPARα and PPARγ by WY14643 and pioglitazone, respectively, attenuated oleate triggered total FFA and TG accumulation in macrophages by repressing FFA import via the suppression of Fatp1 expression. Furthermore, the inhibition of Fatp1 by tumor necrosis factor α alleviated oleate-induced total FFA and TG accumulation in macrophages. This study provided the first demonstration that accumulation of amino acids, nucleosides, lactate, monoacylglycerols, total FFAs, and TGs in oleate-treated macrophages is effectively attenuated or even abolished by resveratrol, and that the activation of PPARα and PPARγ attenuates oleate-induced total FFA and TG accumulation via suppression of Fatp1 expression in macrophages. Therapeutic strategies aim to activate PPAR signaling, and to repress FFA import and triglyceride synthesis are promising approaches to reduce the risk of obesity, diabetes and atherosclerosis.

Dataset Information

Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPAR? and PPAR?.

Publications

Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets