The constitutive androstane receptor activator 4-[(4R,6R)-4,6-diphenyl-1,3- dioxan-2-yl]-N,Ndimethylaniline inhibits the gluconeogenic genes PEPCK and G6Pase through the suppression of HNF4a and FOXO1 transcriptional activity

British Journal of Pharmacology

Volumn 168, Issue 8, 2013, Pages 1923-1932

  Yarushkin, Aa ^a   Kachaylo, Em ^a   Pustylnyak, Vo ^a,b  

^a INSTITUTE OF MOLECULAR BIOLOGY AND BIOPHYSICS   (Russian Federation)

^b NOVOSIBIRSK STATE UNIVERSITY   (Russian Federation)

Author keywords

CAR; FOXO1; G6Pase; gluconeogenesis; HNF4 ; PEPCK

Indexed keywords

2,4,6 TRIPHENYL 1,3 DIOXANE; 4 (4,6 DIPHENYL 1,3 DIOXAN 2 YL) N,N DIMETHYLANILINE; CONSTITUTIVE ANDROSTANE RECEPTOR; GLUCOSE 6 PHOSPHATASE; HEPATOCYTE NUCLEAR FACTOR 4ALPHA; HORMONE RECEPTOR STIMULATING AGENT; PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP); TRANSCRIPTION FACTOR FKHR; UNCLASSIFIED DRUG; 4-(4,6-DIPHENYL-1,3-DIOXAN-2-YL)-N,N-DIMETHYLANILINE; ANILINE DERIVATIVE; CELL RECEPTOR; FORKHEAD TRANSCRIPTION FACTOR; FOXO1 PROTEIN, RAT; GLUCOSE; HEPATOCYTE NUCLEAR FACTOR 4; HNF4A PROTEIN, RAT; INSULIN; N,N-DIMETHYLANILINE; NERVE PROTEIN; PHOSPHOENOLPYRUVATE CARBOXYKINASE 1 (SOLUBLE) PROTEIN, RAT; SIGNAL PEPTIDE; SINGLE HETEROCYCLIC RINGS;

ANIMAL TISSUE; ARTICLE; BINDING SITE; CHROMATIN IMMUNOPRECIPITATION; CONTROLLED STUDY; DRUG STRUCTURE; ENZYME INACTIVATION; ENZYME REPRESSION; G6PASE GENE; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; GLUCOSE TOLERANCE TEST; INSULIN TOLERANCE TEST; MALE; NONHUMAN; PEPCK GENE; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN BINDING; PROTEIN DEGRADATION; RAT; REAL TIME POLYMERASE CHAIN REACTION; SINGLE DRUG DOSE; TRANSACTIVATION; WESTERN BLOTTING; AGONISTS; ANIMAL; DRUG EFFECTS; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENETICS; LIPID DIET; LIVER; METABOLISM; WISTAR RAT;

ANILINE COMPOUNDS; ANIMALS; DIET, HIGH-FAT; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION; GENE EXPRESSION REGULATION; GLUCONEOGENESIS; GLUCOSE; GLUCOSE TOLERANCE TEST; GLUCOSE-6-PHOSPHATASE; HEPATOCYTE NUCLEAR FACTOR 4; HETEROCYCLIC COMPOUNDS, 1-RING; INSULIN; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LIVER; MALE; NERVE TISSUE PROTEINS; PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP); PROMOTER REGIONS, GENETIC; RATS; RATS, WISTAR; RECEPTORS, CYTOPLASMIC AND NUCLEAR;

EID: 84875461047     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12090     Document Type: Article

References (30)

1. Accili D, Arden KC, (2004). FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117: 421-426.
2. Alexander SP, Mathie A, Peters JA, (2011). Guide to Receptors and Channels (GRAC), 5th edition. Br J Pharmacol 164 (Suppl. 1): S1-S324.
3. Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN, et al. (2003). Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab 285: E718-E728.
4. Barthel A, Schmoll D, Unterman TG, (2005). FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab 16: 183-189.
5. Burke MD, Thompson S, Elcombe C, Halpert J, Haaparanta T, Mayer RT, (1985). Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450. Biochem Pharmacol 34: 3337-3345.
6. Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, et al. (2009). Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci U S A 106: 18831-18836.
7. Gao J, He J, Zhai Y, Wada T, Xie W, (2009). The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 284: 25984-25992.
8. Griengl H, Geppert KP, (1976). Prins-reaktionen mit arylaldehyden und Arylolefine. Monatshafte fur Chemie 107: 421-431.
9. Hirota K, Sakamaki J, Ishida J, Shimamoto Y, Nishihara S, Kodama N, et al. (2008). A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding. J Biol Chem 283: 32432-32441.
10. Kachaylo E, Yarushkin A, Pustylnyak V, (2012a). Constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 suppresses the expression of the gluconeogenic genes. Eur J Pharmacol 679: 139-143.
11. Kachaylo EM, Pustylnyak VO, Lyakhovich VV, Gulyaeva LF, (2011). Constitutive androstane receptor (CAR) is a xenosensor and target for therapy. Biochemistry (Mosc) 76: 1087-1097.
12. Kachaylo EM, Yarushkin AA, Pustylnyak VO, (2012b). Long-term constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 improves glucose metabolism in high-fat diet rats. Biochem Anal Biochem S4. doi: 10.4172/2161-1009.S4-001.
13. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, (2010). NC3Rs Reporting Guidelines Working Group. Br J Pharmacol 160: 1577-1579.
14. Kodama S, Koike C, Negishi M, Yamamoto Y, (2004). Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol 24: 7931-7940.
15. Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A, (2003). Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci U S A 100: 11285-11290.
16. McGrath J, Drummond G, McLachlan E, Kilkenny C, Wainwright C, (2010). Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol 160: 1573-1576.
17. Miao J, Fang S, Bae Y, Kemper JK, (2006). Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha. J Biol Chem 281: 14537-14546.
18. Nagashima T, Shigematsu N, Maruki R, Urano Y, Tanaka H, Shimaya A, et al. (2010). Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice. Mol Pharmacol 78: 961-970.
19. Nakae J, Kitamura T, Silver DL, Accili D, (2001). The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest 108: 1359-1367.
20. Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, et al. (2004). Control of pancreas and liver gene expression by HNF transcription factors. Science 303: 1378-1381.
21. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, et al. (2003). Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423: 550-555.
22. Pustylnyak V, Yarushkin A, Kachaylo E, Slynko N, Lyakhovich V, Gulyaeva L, (2011a). Effect of several analogs of 2,4,6-triphenyldioxane-1,3 on constitutive androstane receptor activation. Chem Biol Interact 192: 177-183.
23. Pustylnyak V, Kazakova Y, Yarushkin A, Slynko N, Gulyaeva L, (2011b). Effect of several analogs of 2,4,6-triphenyldioxane-1,3 on CYP2B induction in mouse liver. Chem Biol Interact 194: 134-138.
24. Pustylnyak VO, Gulyaeva LF, Lyakhovich VV, (2007). Induction of cytochrome P4502B: role of regulatory elements and nuclear receptors. Biochemistry (Mosc) 72: 608-617.
25. Qu S, Altomonte J, Perdomo G, He J, Fan Y, Kamagate A, et al. (2006). Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology 147: 5641-5652.
26. Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, et al. (2003). Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci U S A 100: 4012-4017.
27. Ropelle ER, Pauli JR, Cintra DE, Frederico MJ, de, Pinho RA, Velloso LA, et al. (2009). Acute exercise modulates the Foxo1/PGC-1alpha pathway in the liver of diet-induced obesity rats. J Physiol 587: 2069-2076.
28. Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, et al. (2002). Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 61: 1-6.
29. Wajngot A, Chandramouli V, Schumann WC, Ekberg K, Jones PK, Efendic S, et al. (2001). Quantitative contributions of gluconeogenesis to glucose production during fasting in type 2 diabetes mellitus. Metabolism 50: 47-52.
30. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, et al. (2001). Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413: 131-138.