1. Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor.
- Author
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Yu L, Wang Z, Huang M, Li Y, Zeng K, Lei J, Hu H, Chen B, Lu J, Xie W, and Zeng S
- Subjects
- Alkaloids isolation & purification, Alkaloids pharmacology, Animals, Constitutive Androstane Receptor, Dose-Response Relationship, Drug, Forkhead Box Protein O1 genetics, Forkhead Box Protein O1 metabolism, Gene Expression Regulation, Gluconeogenesis genetics, Glucose metabolism, Glucose-6-Phosphatase genetics, Glucose-6-Phosphatase metabolism, Hep G2 Cells, Hepatocyte Nuclear Factor 4 genetics, Hepatocyte Nuclear Factor 4 metabolism, Hepatocytes cytology, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Hypoglycemic Agents isolation & purification, Indole Alkaloids isolation & purification, Lipogenesis genetics, Liver cytology, Liver drug effects, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphoenolpyruvate Carboxykinase (ATP) genetics, Phosphoenolpyruvate Carboxykinase (ATP) metabolism, Primary Cell Culture, Quinazolines isolation & purification, Receptors, Cytoplasmic and Nuclear agonists, Receptors, Cytoplasmic and Nuclear metabolism, Signal Transduction, Evodia chemistry, Gluconeogenesis drug effects, Hypoglycemic Agents pharmacology, Indole Alkaloids pharmacology, Lipogenesis drug effects, Quinazolines pharmacology, Receptors, Cytoplasmic and Nuclear genetics
- Abstract
The constitutive androstane receptor (CAR) is a key sensor in xenobiotic detoxification and endobiotic metabolism. Increasing evidence suggests that CAR also plays a role in energy metabolism by suppressing the hepatic gluconeogenesis and lipogenesis. In this study, we investigated the effects of two evodia alkaloids, rutaecarpine (Rut) and evodiamine (Evo), on gluconeogenesis and lipogenesis through their activation of the human CAR (hCAR). We found that both Rut and Evo exhibited anti-lipogenic and anti-gluconeogenic effects in the hyperlipidemic HepG2 cells. Both compounds can potently activate hCAR, and treatment of cells with hCAR antagonists reversed the anti-lipogenic and anti-gluconeogenic effects of Rut and Evo. The anti-gluconeogenic effect of Rut and Evo was due to the CAR-mediated inhibition of the recruitment of forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4α (HNF4α) onto the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene promoters. In vivo, we showed that treatment of mice with Rut improved glucose tolerance in a CAR-dependent manner. Our results suggest that the evodia alkaloids Rut and Evo may have a therapeutic potential for the treatment of hyperglycemia and type 2 diabetes. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2016
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