726
Views
34
CrossRef citations to date
0
Altmetric
Reviews

Targeting PPARβ/δ for the treatment of type 2 diabetes mellitus

, , , &
Pages 209-223 | Published online: 27 Jan 2012

Bibliography

  • Laudet V, Auwerx J, Gustafsson J-A, Wahli W. A unified nomenclature system for the nuclear receptor superfamily. Cell 1999;97:161-3
  • de DC, Beaufay H, Jacques P, Intracellular localization of catalase and of some oxidases in rat liver. Biochim Biophys Acta 1960;40:186-7
  • Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990;347:645-50
  • Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999;20:649-88
  • Moraes LA, Piqueras L, Bishop-Bailey D. Peroxisome proliferator-activated receptors and inflammation. Pharmacol Ther 2006;110:371-85
  • Zamir I, Zhang J, Lazar MA. Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes Dev 1997;11:835-46
  • Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000;49:497-505
  • Feige JN, Gelman L, Michalik L, From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 2006;45:120-59
  • Wadosky KM, Willis MS. The story so far: post-translational regulation of peroxisome proliferator-activated receptors (PPARs) by ubiquitination and SUMOylation. Am J Physiol Heart Circ Physiol 2011; in press
  • Pascual G, Fong AL, Ogawa S, A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 2005;437:759-63
  • Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002;2:748-59
  • Kamei Y, Xu L, Heinzel T, A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 1996;85:403-14
  • Li M, Pascual G, Glass CK. Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Mol Cell Biol 2000;20:4699-707
  • Delerive P, De BK, Besnard S, Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 1999;274:32048-54
  • Delerive P, Martin-Nizard F, Chinetti G, Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 1999;85:394-402
  • Desreumaux P, Dubuquoy L, Nutten S, Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J Exp Med 2001;193:827-38
  • Johnson TE, Holloway MK, Vogel R, Structural requirements and cell-type specificity for ligand activation of peroxisome proliferator-activated receptors. J Steroid Biochem Mol Biol 1997;63:1-8
  • Devchand PR, Keller H, Peters JM, The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 1996;384:39-43
  • Narala VR, Adapala RK, Suresh MV, Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist. J Biol Chem 2010;285:22067-74
  • Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem 2000;275:36703-7
  • Keller H, Dreyer C, Medin J, Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci USA 1993;90:2160-4
  • Gulick T, Cresci S, Caira T, The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci USA 1994;91:11012-16
  • Gervois P, Torra IP, Fruchart JC, Staels B. Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin Chem Lab Med 2000;38:3-11
  • Vu-Dac N, Gervois P, Jakel H, Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators. J Biol Chem 2003;278:17982-5
  • Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994;79:1147-56
  • Rosen ED, Sarraf P, Troy AE, PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611-17
  • Kubota N, Terauchi Y, Miki H, PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999;4:597-609
  • He W, Barak Y, Hevener A, Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 2003;100:15712-17
  • Dreyer C, Krey G, Keller H, Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 1992;68:879-87
  • Schmidt A, Endo N, Rutledge SJ, Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol 1992;6:1634-41
  • Kliewer SA, Forman BM, Blumberg B, Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 1994;91:7355-9
  • Amri EZ, Bonino F, Ailhaud G, Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem 1995;270:2367-71
  • Escher P, Braissant O, Basu-Modak S, Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 2001;142:4195-202
  • Girroir EE, Hollingshead HE, He P, Quantitative expression patterns of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) protein in mice. Biochem Biophys Res Commun 2008;371:456-61
  • Takada I, Yu RT, Xu HE, Alteration of a single amino acid in peroxisome proliferator-activated receptor-alpha (PPAR alpha) generates a PPAR delta phenotype. Mol Endocrinol 2000;14:733-40
  • Xu HE, Lambert MH, Montana VG, Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999;3:397-403
  • Forman BM, Ruan B, Chen J, The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism. Proc Natl Acad Sci USA 1997;94:10588-93
  • Yu K, Bayona W, Kallen CB, Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem 1995;270:23975-83
  • Krey G, Braissant O, L'Horset F, Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 1997;11:779-91
  • Chawla A, Lee CH, Barak Y, PPARdelta is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci USA 2003;100:1268-73
  • Shaw N, Elholm M, Noy N. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. J Biol Chem 2003;278:41589-92
  • Rieck M, Meissner W, Ries S, Ligand-mediated regulation of peroxisome proliferator-activated receptor (PPAR) beta/delta: a comparative analysis of PPAR-selective agonists and all-trans retinoic acid. Mol Pharmacol 2008;74:1269-77
  • Borland MG, Foreman JE, Girroir EE, Ligand activation of peroxisome proliferator-activated receptor-beta/delta inhibits cell proliferation in human HaCaT keratinocytes. Mol Pharmacol 2008;74:1429-42
  • Berger J, Leibowitz MD, Doebber TW, Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem 1999;274:6718-25
  • Sznaidman ML, Haffner CD, Maloney PR, Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)–synthesis and biological activity. Bioorg Med Chem Lett 2003;13:1517-21
  • Shearer BG, Steger DJ, Way JM, Identification and characterization of a selective peroxisome proliferator-activated receptor beta/delta (NR1C2) antagonist. Mol Endocrinol 2008;22:523-9
  • Surampudi PN, John-Kalarickal J, Fonseca VA. Emerging concepts in the pathophysiology of type 2 diabetes mellitus. Mt Sinai J Med 2009;76:216-26
  • Tripathy D, Chavez AO. Defects in insulin secretion and action in the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep 2010;10:184-91
  • Nalysnyk L, Hernandez-Medina M, Krishnarajah G. Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature. Diabetes Obes Metab 2010;12:288-98
  • Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008;28:629-36
  • Mathieu P, Lemieux I, Despres JP. Obesity, inflammation, and cardiovascular risk. Clin Pharmacol Ther 2010;87:407-16
  • Mathieu P, Pibarot P, Despres JP. Metabolic syndrome: the danger signal in atherosclerosis. Vasc Health Risk Manag 2006;2:285-302
  • Boden G, Jadali F, White J, Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest 1991;88:960-6
  • Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997;46:3-10
  • Shi H, Kokoeva MV, Inouye K, TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015-25
  • Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783-801
  • Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793-801
  • Nguyen MT, Favelyukis S, Nguyen AK, A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 2007;282:35279-92
  • Cani PD, Amar J, Iglesias MA, Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761-72
  • Rodriguez-Calvo R, Serrano L, Coll T, Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2. Diabetes 2008;57:2149-57
  • Chung S, Lapoint K, Martinez K, Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology 2006;147:5340-51
  • Barbarroja N, Lopez-Pedrera R, Mayas MD, The obese healthy paradox: is inflammation the answer? Biochem J 2010;430:141-9
  • Vozarova B, Weyer C, Hanson K, Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res 2001;9:414-17
  • Kern PA, Ranganathan S, Li C, Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001;280:E745-51
  • Pradhan AD, Manson JE, Rifai N, C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327-34
  • Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology 2005;146:3417-27
  • Heinrich PC, Behrmann I, Haan S, Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003;374:1-20
  • Kamimura D, Ishihara K, Hirano T. IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 2003;149:1-38
  • Ernst M, Jenkins BJ. Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet 2004;20:23-32
  • Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000;19:2468-73
  • Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995;82:241-50
  • Zhang X, Blenis J, Li HC, Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science 1995;267:1990-4
  • Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene 2000;19:2628-37
  • He HJ, Zhu TN, Xie Y, Pyrrolidine dithiocarbamate inhibits interleukin-6 signaling through impaired STAT3 activation and association with transcriptional coactivators in hepatocytes. J Biol Chem 2006;281:31369-79
  • Starr R, Willson TA, Viney EM, A family of cytokine-inducible inhibitors of signalling. Nature 1997;387:917-21
  • Emanuelli B, Peraldi P, Filloux C, SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 2001;276:47944-9
  • Emanuelli B, Peraldi P, Filloux C, SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 2000;275:15985-91
  • Rui L, Yuan M, Frantz D, SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 2002;277:42394-8
  • Lagathu C, Bastard JP, Auclair M, Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun 2003;311:372-9
  • Shi H, Tzameli I, Bjorbaek C, Flier JS. Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. J Biol Chem 2004;279:34733-40
  • Serrano-Marco L, Rodriguez-Calvo R, El Kochairi I, Activation of peroxisome proliferator-activated receptor-{beta}/-{delta} (PPAR-{beta}/-{delta}) ameliorates insulin signaling and reduces SOCS3 levels by inhibiting STAT3 in Interleukin-6-stimulated adipocytes. Diabetes 2011;60:1990-9
  • Peters JM, Lee SS, Li W, Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta). Mol Cell Biol 2000;20:5119-28
  • Bortolotto JW, Margis R, Ferreira AC, Adipose tissue distribution and quantification of PPARbeta/delta and PPARgamma1-3 mRNAs: discordant gene expression in subcutaneous, retroperitoneal and visceral adipose tissue of morbidly obese patients. Obes Surg 2007;17:934-40
  • Kang K, Reilly SM, Karabacak V, Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 2008;7:485-95
  • Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003;3:23-35
  • Roden M, Perseghin G, Petersen KF, The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans. J Clin Invest 1996;97:642-8
  • Haber EP, Hirabara SM, Gomes AD, Palmitate modulates the early steps of insulin signalling pathway in pancreatic islets. FEBS Lett 2003;544:185-8
  • Silveira LR, Fiamoncini J, Hirabara SM, Updating the effects of fatty acids on skeletal muscle. J Cell Physiol 2008;217:1-12
  • Hirabara SM, Silveira LR, Abdulkader F, Time-dependent effects of fatty acids on skeletal muscle metabolism. J Cell Physiol 2007;210:7-15
  • Roden M, Price TB, Perseghin G, Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996;97:2859-65
  • Haber EP, Hirabara SM, Gomes AD, Palmitate modulates the early steps of insulin signalling pathway in pancreatic islets. FEBS Lett 2003;544:185-8
  • Schrauwen P, Schrauwen-Hinderling V, Hoeks J, Hesselink MK. Mitochondrial dysfunction and lipotoxicity. Biochim Biophys Acta 2010;1801:266-71
  • Hirabara SM, Curi R, Maechler P. Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. J Cell Physiol 2010;222:187-94
  • Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111-19
  • Griffin ME, Marcucci MJ, Cline GW, Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999;48:1270-4
  • Cortright RN, Azevedo JL, Zhou Q, Protein kinase C modulates insulin action in human skeletal muscle. Am J Physiol-Endocrinol Metab 2000;278:E553-62
  • Itani SI, Zhou Q, Pories WJ, Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes 2000;49:1353-8
  • Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005;87:99-109
  • Hotamisligil GS, Peraldi P, Budavari A, IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996;271:665-8
  • Perseghin G, Petersen K, Shulman GI. Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes 2003;27:S6-S11
  • Kim JK, Kim YJ, Fillmore JJ, Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001;108:437-46
  • Yuan MS, Konstantopoulos N, Lee JS, Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKK beta. Science 2001;293:1673-7
  • Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997;40:1286-92
  • Reznick RM, Shulman GI. The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol 2006;574:33-9
  • Sebastian D, Herrero L, Serra D, CPT I overexpression protects L6E9 muscle cells from fatty acid-induced insulin resistance. Am J Physiol Endocrinol Metab 2007;292:E677-86
  • Bruce CR, Hoy AJ, Turner N, Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes 2009;58:550-8
  • Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590-7
  • Kramer DK, Al-Khalili L, Guigas B, Role of AMP kinase and PPARdelta in the regulation of lipid and glucose metabolism in human skeletal muscle. J Biol Chem 2007;282:19313-20
  • Coll T, Varez-Guardia D, Barroso E, Activation of peroxisome proliferator-activated receptor-{delta} by GW501516 prevents fatty acid-induced nuclear factor-{kappa}B activation and insulin resistance in skeletal muscle cells. Endocrinology 2010;151:1560-9
  • Riserus U, Sprecher D, Johnson T, Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 2008;57:332-9
  • Sprecher DL, Massien C, Pearce G, Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Arterioscler Thromb Vasc Biol 2007;27:359-65
  • Luquet S, Lopez-Soriano J, Holst D, Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J 2003;17:2299-301
  • Schuler M, Ali F, Chambon C, PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab 2006;4:407-14
  • Higashiura K, Ura N, Takada T, Alteration of muscle fiber composition linking to insulin resistance and hypertension in fructose-fed rats. Am J Hypertens 1999;12:596-602
  • Giordano C, Rousseau AS, Wagner N, Peroxisome proliferator-activated receptor beta activation promotes myonuclear accretion in skeletal muscle of adult and aged mice. Pflugers Arch 2009;458:901-13
  • Li P, Akimoto T, Zhang M, Resident stem cells are not required for exercise-induced fiber-type switching and angiogenesis but are necessary for activity-dependent muscle growth. Am J Physiol Cell Physiol 2006;290:C1461-8
  • Del PS. Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies. Diabet Med 2009;26:1185-92
  • Daoudi M, Hennuyer N, Borland MG, PPARbeta/delta activation induces enteroendocrine L cell GLP-1 production. Gastroenterology 2011;140:1564-74
  • Cohen G, Riahi Y, Shamni O, Role of lipid peroxidation and PPAR-{delta} in amplifying glucose-stimulated insulin secretion. Diabetes 2011;60:2830-42
  • Winzell MS, Wulff EM, Olsen GS, Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice. Eur J Pharmacol 2010;626:297-305
  • Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 1999;274:30028-32
  • Yang T, Espenshade PJ, Wright ME, Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002;110:489-500
  • Qin X, Xie X, Fan Y, Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 2008;48:432-41
  • Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421
  • Barter P, Gotto AM, LaRosa JC, HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10
  • Miller M, Cannon CP, Murphy SA, Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724-30
  • Fruchart JC, Sacks FM, Hermans MP, The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35
  • Shepherd J, Barter P, Carmena R, Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220-6
  • Grundy SM. Atherogenic dyslipidemia: lipoprotein abnormalities and implications for therapy. Am J Cardiol 1995;75:45B-52B
  • Shepherd J, Betteridge J, Van GL. Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel. Curr Med Res Opin 2005;21:665-82
  • Adiels M, Olofsson SO, Taskinen MR, Boren J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008;28:1225-36
  • Chan DC, Watts GF. Dyslipidaemia in the metabolic syndrome and type 2 diabetes: pathogenesis, priorities, pharmacotherapies. Expert Opin Pharmacother 2011;12:13-30
  • Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003;46:733-49
  • Akiyama TE, Lambert G, Nicol CJ, Peroxisome proliferator-activated receptor beta/delta regulates very low density lipoprotein production and catabolism in mice on a Western diet. J Biol Chem 2004;279:20874-81
  • Barroso E, Rodriguez-Calvo R, Serrano-Marco L, The PPAR{beta}/{delta} activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1{alpha}-Lipin 1-PPAR{alpha} pathway leading to increased fatty acid oxidation. Endocrinology 2011;152:1848-59
  • Lewis GF. Fatty acid regulation of very low density lipoprotein production. Curr Opin Lipidol 1997;8:146-53
  • Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 2009;9:407-16
  • Bou KM, Sundaram M, Zhang HY, The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL. J Lipid Res 2009;50:47-58
  • Finck BN, Gropler MC, Chen Z, Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 2006;4:199-210
  • Oliver WR Jr, Shenk JL, Snaith MR, A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 2001;98:5306-11
  • Chakravarthy MV, Lodhi IJ, Yin L, Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell 2009;138:476-88
  • Tanaka T, Yamamoto J, Iwasaki S, Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci USA 2003;100:15924-9
  • Wang YX, Lee CH, Tiep S, Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003;113:159-70
  • Lee CH, Olson P, Hevener A, PPARdelta regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci USA 2006;103:3444-9
  • Ooi EM, Watts GF, Sprecher DL, Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity. J Clin Endocrinol Metab 2011;96:E1568-76
  • Kino T, Rice KC, Chrousos GP. The PPARdelta agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition. Eur J Clin Invest 2007;37:425-33
  • Planavila A, Rodriguez-Calvo R, Jove M, Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes. Cardiovasc Res 2005;65:832-41
  • varez-Guardia D, Palomer X, Coll T, PPARbeta/delta activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells. Biochim Biophys Acta 2011;1811:59-67
  • Cheng L, Ding G, Qin Q, Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 2004;10:1245-50
  • Reed KR, Sansom OJ, Hayes AJ, PPARdelta status and Apc-mediated tumourigenesis in the mouse intestine. Oncogene 2004;23:8992-6
  • Harman FS, Nicol CJ, Marin HE, Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat Med 2004;10:481-3
  • Gupta S, Purcell NH, Lin AN, Sen S. Activation of nuclear factor-kappa B is necessary for myotrophin-induced cardiac hypertrophy. J Cell Biol 2002;159:1019-28
  • Park BH, Vogelstein B, Kinzler KW. Genetic disruption of PPARdelta decreases the tumorigenicity of human colon cancer cells. Proc Natl Acad Sci USA 2001;98:2598-603
  • Peters JM, Hollingshead HE, Gonzalez FJ. Role of peroxisome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease. Clin Sci (Lond) 2008;115:107-27
  • Peters JM, Gonzalez FJ. Sorting out the functional role(s) of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) in cell proliferation and cancer. Biochim Biophys Acta 2009;1796:230-41
  • Peters JM, Foreman JE, Gonzalez FJ. Dissecting the role of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) in colon, breast, and lung carcinogenesis. Cancer Metastasis Rev 2011;30:619-40
  • Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care 2011;34:1369-71
  • Klaunig JE, Babich MA, Baetcke KP, PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol 2003;33:655-780
  • Peters JM, Cheung C, Gonzalez FJ. Peroxisome proliferator-activated receptor-alpha and liver cancer: where do we stand? J Mol Med (Berl) 2005;83:774-85

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.