title: Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor.
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.
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Lushan
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Zhangting
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Zeng
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Jinxiu
authors.initials: J
authors.lastname: Lei
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, China.
authors.forename: Baian
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wex6@pitt.edu.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Electronic address: zengsu@zju.edu.cn.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D000090702:Constitutive Androstane Receptor; D004305:Dose-Response Relationship, Drug; D032086:Evodia / Q000737:chemistry*; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D026121:Indole Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011799:Quinazolines / Q000302:isolation & purification / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D052999:Quinazolinones
chemical_list: D000470:Alkaloids; D000090702:Constitutive Androstane Receptor; D000071161:Forkhead Box Protein O1; D005947:Glucose; D005952:Glucose-6-Phosphatase; D051557:Hepatocyte Nuclear Factor 4; D007004:Hypoglycemic Agents; D026121:Indole Alkaloids; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D011799:Quinazolines; D018160:Receptors, Cytoplasmic and Nuclear; C467200:Foxo1 protein, mouse; C496593:Hnf4a protein, mouse; C028632:rutecarpine; D052999:Quinazolinones; C049639:evodiamine
keywords: Constitutive androstane receptor; Evodiamine; Gluconeogenesis; Lipogenesis; Rutaecarpine