Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

Toxicology and Applied Pharmacology

Volumn 279, Issue 1, 2014, Pages 33-42

  Lynch, Caitlin ^a   Pan, Yongmei ^a   Li, Linhao ^a   Heyward, Scott ^b   Moeller, Timothy ^b   Swaan, Peter W ^a   Wang, Hongbing ^a  

^a UNIVERSITY OF MARYLAND SCHOOL OF PHARMACY   (United States)

^b In Vitro Technologies Inc   (United States)

Author keywords

Constitutive androstane receptor; Energy metabolism; Human primary hepatocytes; Species difference

Indexed keywords

ANTIDIABETIC AGENT; CONSTITUTIVE ANDROSTANE RECEPTOR; CYTOCHROME P450 2B6; FATTY ACID; GLUCOSE; GLUCOSE 6 PHOSPHATASE; PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP); STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; UM 104; UM 145; UNCLASSIFIED DRUG;

ANIMAL CELL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG CYTOTOXICITY; ENERGY METABOLISM; FATTY ACID SYNTHESIS; GENE EXPRESSION; GENETIC ASSOCIATION; GLUCONEOGENESIS; GLUCOSE HOMEOSTASIS; HUMAN; HUMAN CELL; LIVER CELL; MALE; MOUSE; NONHUMAN; PHARMACOPHORE; PROTEIN EXPRESSION; REAL TIME POLYMERASE CHAIN REACTION; RECEIVER OPERATING CHARACTERISTIC; SPECIES DIFFERENCE; TRANSIENT TRANSFECTION; WESTERN BLOTTING;

CONSTITUTIVE ANDROSTANE RECEPTOR; ENERGY METABOLISM; HUMAN PRIMARY HEPATOCYTES; SPECIES DIFFERENCE;

ANIMALS; BLOTTING, WESTERN; CELL LINE; COMPUTER SIMULATION; ENERGY METABOLISM; FATTY ACIDS; GLUCONEOGENESIS; GLUCOSE; GLUCOSE-6-PHOSPHATASE; HEPATOCYTES; HUMANS; LIPOGENESIS; MALE; MICE; MICE, INBRED C57BL; MODELS, MOLECULAR; PHOSPHOENOLPYRUVATE CARBOXYKINASE (ATP); PRIMARY CELL CULTURE; PROTEIN TRANSPORT; REAL-TIME POLYMERASE CHAIN REACTION; RECEPTORS, CYTOPLASMIC AND NUCLEAR; TRIGLYCERIDES;

EID: 84902285196     PISSN: 0041008X     EISSN: 10960333     Source Type: Journal    
DOI: 10.1016/j.taap.2014.05.009     Document Type: Article

References (41)

1. Auerbach S.S., Stoner M.A., Su S., Omiecinski C.J. Retinoid X receptor-α-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3). Mol. Pharmacol. 2005, 68:1239-1253.
2. Baskin-Bey E.S., Anan A., Isomoto H., Bronk S.F., Gores G.J. Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse. World J. Gastroenterol. 2007, 13:5635-5641.
3. Chakraborty S., Kanakasabai S., Bright J.J. Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells. Br. J. Cancer 2011, 104:448-459.
4. Chang C., Bahadduri P.M., Polli J.E., Swaan P.W., Ekins S. Rapid identification of P-glycoprotein substrates and inhibitors. Drug Metab. Dispos. 2006, 34:1976-1984.
5. Chen T., Tompkins L.M., Li L., Li H., Kim G., Zheng Y., Wang H. A single amino acid controls the functional switch of human constitutive androstane receptor (CAR) 1 to the xenobiotic-sensitive splicing variant CAR3. J. Pharmacol. Exp. Ther. 2010, 332:106-115.
6. Dong B., Saha P.K., Huang W., Chen W., Abu-Elheiga L.A., Wakil S.J., Stevens R.D., Ilkayeva O., Newgard C.B., Chan L., Moore D.D. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:18831-18836.
7. Gao J., Xie W. Pregnane X receptor and constitutive androstane receptor at the crossroads of drug metabolism and energy metabolism. Drug Metab. Dispos. 2010, 38:2091-2095.
8. Gao J., He J., Zhai Y., Wada T., Xie W. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J. Biol. Chem. 2009, 284:25984-25992.
9. Huang W., Zhang J., Wei P., Schrader W.T., Moore D.D. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol. Endocrinol. 2004, 18:2402-2408.
10. Huang W., Zhang J., Washington M., Liu J., Parant J.M., Lozano G., Moore D.D. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol. Endocrinol. 2005, 19:1646-1653.
11. Jain A.N. Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities. J. Comput. Aided Mol. Des. 1996, 10:427-440.
12. Kakizaki S., Takizawa D., Tojima H., Yamazaki Y., Mori M. Xenobiotic-sensing nuclear receptors CAR and PXR as drug targets in cholestatic liver disease. Curr. Drug Targets 2009, 10:1156-1163.
13. Kawamoto T., Sueyoshi T., Zelko I., Moore R., Washburn K., Negishi M. Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol. Cell. Biol. 1999, 19:6318-6322.
14. Kodama S., Koike C., Negishi M., Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol. Cell. Biol. 2004, 24:7931-7940.
15. Li H., Wang H. Activation of Xenobiotic Receptors: Driving Into the Nucleus 2010, 409-426.
16. Li A.P., Lu C., Brent J.A., Pham C., Fackett A., Ruegg C.E., Silber P.M. Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem. Biol. Interact. 1999, 121:17-35.
17. Li L., Chen T., Stanton J.D., Sueyoshi T., Negishi M., Wang H. The peripheral benzodiazepine receptor ligand 1-(2-chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide is a novel antagonist of human constitutive androstane receptor. Mol. Pharmacol. 2008, 74:443-453.
18. Li H., Chen T., Cottrell J., Wang H. Nuclear translocation of adenoviral-enhanced yellow fluorescent protein-tagged-human constitutive androstane receptor (hCAR): a novel tool for screening hCAR activators in human primary hepatocytes. Drug Metab. Dispos. 2009, 37:1098-1106.
19. Lynch C., Pan Y., Li L., Ferguson S., Xia M., Swaan P., Wang H. Identification of novel activators of constitutive androstane receptor from FDA-approved drugs by integrated computational and biological approaches. Pharm. Res. 2013, 30:489-501.
20. Maglich J.M., Parks D.J., Moore L.B., Collins J.L., Goodwin B., Billin A.N., Stoltz C.A., Kliewer S.A., Lambert M.H., Willson T.M., Moore J.T. Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J. Biol. Chem. 2003, 278:17277-17283.
21. Maglich J.M., Watson J., McMillen P.J., Goodwin B., Willson T.M., Moore J.T. The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J. Biol. Chem. 2004, 279:19832-19838.
22. Moreau A., Vilarem M.J., Maurel P., Pascussi J.M. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol. Pharm. 2008, 5:35-41.
23. Moya M., Gomez-Lechon M.J., Castell J.V., Jover R. Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile. Chem. Biol. Interact. 2010, 184:376-387.
24. Mues C., Zhou J., Manolopoulos K.N., Korsten P., Schmoll D., Klotz L.O., Bornstein S.R., Klein H.H., Barthel A. Regulation of glucose-6-phosphatase gene expression by insulin and metformin. Horm. Metab. Res. 2009, 41:730-735.
25. Pan Y., Li L., Kim G., Ekins S., Wang H., Swaan P.W. Identification and validation of novel human pregnane X receptor activators among prescribed drugs via ligand-based virtual screening. Drug Metab. Dispos. 2011, 39:337-344.
26. Pan Y., Chothe P.P., Swaan P.W. Identification of novel breast cancer resistance protein (BCRP) inhibitors by virtual screening. Mol. Pharm. 2013, 10:1236-1248.
27. Qatanani M., Moore D.D. CAR, the continuously advancing receptor, in drug metabolism and disease. Curr. Drug Metab. 2005, 6:329-339.
28. Rogers D., Brown R.D., Hahn M. Using extended-connectivity fingerprints with Laplacian-modified Bayesian analysis in high-throughput screening follow-up. J. Biomol. Screen. 2005, 10:682-686.
29. Swift B., Brouwer K.L. Influence of seeding density and extracellular matrix on bile acid transport and Mrp4 expression in sandwich-cultured mouse hepatocytes. Mol. Pharm. 2010, 7:491-500.
30. Timsit Y.E., Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids 2007, 72:231-246.
31. Tolson A.H., Wang H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv. Drug Deliv. Rev. 2010, 62:1238-1249.
32. Tzameli I., Pissios P., Schuetz E.G., Moore D.D. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol. Cell. Biol. 2000, 20:2951-2958.
33. Ueda A., Hamadeh H.K., Webb H.K., Yamamoto Y., Sueyoshi T., Afshari C.A., Lehmann J.M., Negishi M. Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol. Pharmacol. 2002, 61:1-6.
34. Wada T., Gao J., Xie W. PXR and CAR in energy metabolism. Trends Endocrinol. Metab. 2009, 20:273-279.
35. Wang H., LeCluyse E.L. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin. Pharmacokinet. 2003, 42:1331-1357.
36. Wang H., Negishi M. Transcriptional regulation of cytochrome P450 2B genes by nuclear receptors. Curr. Drug Metab. 2003, 4:515-525.
37. Yamamoto Y., Kawamoto T., Negishi M. The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity. Arch. Biochem. Biophys. 2003, 409:207-211.
38. Yamamoto Y., Moore R., Goldsworthy T.L., Negishi M., Maronpot R.R. The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res. 2004, 64:7197-7200.
39. Yamazaki Y., Kakizaki S., Horiguchi N., Sohara N., Sato K., Takagi H., Mori M., Negishi M. The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 2007, 56:565-574.
40. Yu P., Wild D.J. Discovering associations in biomedical datasets by link-based associative classifier (LAC). PLoS ONE 2012, 7:e51018.
41. Zhai Y., Wada T., Zhang B., Khadem S., Ren S., Kuruba R., Li S., Xie W. A functional cross-talk between liver X receptor-alpha and constitutive androstane receptor links lipogenesis and xenobiotic responses. Mol. Pharmacol. 2010, 78:666-674.