Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor γ (PPARγ) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes

Diabetologia

Volumn 56, Issue 2, 2013, Pages 401-411

  Zheng, W ^a   Feng, X ^a   Qiu, L ^a   Pan, Z ^a   Wang, R ^a   Lin, S ^a   Hou, D ^a   Jin, L ^a   Li, Y ^a  

^a XIAMEN UNIVERSITY   (China)

Author keywords

Crystal structure; Diabetes; Ionomycin; Nuclear receptor; PPAR

Indexed keywords

2 CHLORO 5 NITROBENZANILIDE; CYCLIN DEPENDENT KINASE 5; EPITOPE; GLUCOSE; IONOMYCIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; SERINE; 2-CHLORO-5-NITROBENZANILIDE; ANILIDE; ANTIDIABETIC AGENT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIDIABETIC ACTIVITY; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; CRYSTAL STRUCTURE; DIABETES MELLITUS; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; EXPERIMENTAL MOUSE; GLUCOSE BLOOD LEVEL; HYPERGLYCEMIA; IN VITRO STUDY; IN VIVO STUDY; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIGAND BINDING; MALE; MOLECULAR MODEL; MOUSE; NONHUMAN; PHARMACOLOGICAL BLOCKING; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; ANIMAL; CHEMISTRY; DRUG EFFECT; DRUG POTENTIATION; HUMAN; METABOLISM; PROTEIN BINDING;

ANILIDES; ANIMALS; BLOOD GLUCOSE; HUMANS; HYPOGLYCEMIC AGENTS; IONOMYCIN; MALE; MICE; PPAR GAMMA; PROTEIN BINDING;

MLCS; MLOWN;

EID: 84878808621     PISSN: 0012186X     EISSN: 14320428     Source Type: Journal    
DOI: 10.1007/s00125-012-2777-9     Document Type: Article

References (38)

1. Michalik L, Auwerx J, Berger JP et al (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev 58:726-741
2. Jin L, Li Y (2010) Structural and functional insights into nuclear receptor signaling. Adv Drug Deliv Rev 62:1218-1226
3. Tontonoz P, Spiegelman BM (2008) Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77:289-312
4. Kuda O, Jelenik T, Jilkova Z et al (2009) n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia 52:941-951
5. Lennon R, Welsh GI, Singh A et al (2009) Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1. Diabetologia 52:1944-1952
6. Serrano-Marco L, Barroso E, El Kochairi I et al (2012) The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia 55:743-751
7. Lehrke M, Lazar MA (2005) The many faces of PPARgamma. Cell 123:993-999
8. Wang YX (2010) PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res 20:124-137
9. Weismann D, Erion DM, Ignatova-Todorava I et al (2011) Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance. Diabetologia 54:935-944
10. Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106-1118
11. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457-2471
12. Zanchi A, Maillard M, Jornayvaz FR et al (2010) Effects of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals. Diabetologia 53:1568-1575
13. Evans RM, Barish GD, Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10:355-361
14. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (2006) From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45:120-159
15. Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10:384-391
16. Allen T, Zhang F, Moodie SA et al (2006) Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity. Diabetes 55:2523-2533
17. Zhang F, Lavan BE, Gregoire FM (2007) Selective modulators of PPAR-γ activity: molecular aspects related to obesity and side-effects. PPAR Res 2007:32696
18. Higgins LS, Depaoli AM (2010) Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation. Am J Clin Nutr 91:267S-272S
19. Choi JH, Banks AS, Estall JL et al (2010) Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 466:451-456
20. Houtkooper RH, Auwerx J (2010) Obesity: new life for antidiabetic drugs. Nature 466:443-444
21. Li P, Fan W, Xu J et al (2011) Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell 147:815-826
22. Otwinowski Z, Minor W (1997) Processing of x-ray diffraction data collected in oscillation mode. Method Enzymol 276:307-326
23. Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60:2126-2132
24. Li Y, Suino K, Daugherty J, Xu HE (2005) Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Mol Cell 19:367-380
25. Li Y, Choi M, Cavey G et al (2005) Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol Cell 17:491-502
26. Jin L, Lin S, Rong H et al (2011) Structural basis for iloprost as a dual peroxisome proliferator-activated receptor alpha/delta agonist. J Biol Chem 286:31473-31479
27. Lin S, Han Y, Shi Y et al (2012) Revealing a steroid receptor ligand as a unique PPARgamma agonist. Cell Res 22:746-756
28. Leesnitzer LM, Parks DJ, Bledsoe RK et al (2002) Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41:6640-6650
29. Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147-1156
30. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM (1994) mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8:1224-1234
31. Gampe RT Jr, Montana VG, Lambert MH et al (2000) Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell 5:545-555
32. Chandra V, Huang P, Hamuro Y et al (2008) Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 456:350-356
33. Nolte RT, Wisely GB, Westin S et al (1998) Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395:137-143
34. Liu C, Hermann TE (1978) Characterization of ionomycin as a calcium ionophore. J Biol Chem 253:5892-5894
35. Oberfield JL, Collins JL, Holmes CP et al (1999) A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation. Proc Natl Acad Sci USA 96:6102-6106
36. Itoh T, Fairall L, Amin K et al (2008) Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat Struct Mol Biol 15:924-931
37. Li Y, Zhang J, Schopfer FJ et al (2008) Molecular recognition of nitrated fatty acids by PPAR gamma. Nat Struct Mol Biol 15:865-867
38. Weidner C, de Groot JC, Prasad A et al (2012) Amorfrutins are potent antidiabetic dietary natural products. Proc Natl Acad Sci USA 109:7257-7262