- Email: [email protected]
PPAR delta: an uncompletely known nuclear receptor
MINI
R E V I E W
PPAR delta: an uncompletely known nuclear receptor A Fredenrich1,2, PA Grimaldi1
SUMMARY
RÉSUMÉ
Peroxisome proliferator-activated receptors (PPAR) mediate some of the transcriptional effects of fatty acids and control many physiological functions, especially in the field of development and metabolism. Three isotypes are known, D, J, and E/G. Roles of PPAR D and PPARJ are now quite well-known, particularly since their pharmacologic ligands have been marketed, respectively the lipid-normalizing class of fibrates and the antidiabetic class of thiazolidinediones (glitazones). However, functions of PPARG are uncompletely known to date, but some recent data enlight its role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue. Overexpression of PPARG using a transgenic murine model promotes an increase of muscle oxidative capability. This is accompanied by a redistribution of fatty acid flux, redirected from adipose tissue towards skeletal muscle. Finally, adipose mass is reduced, due to a decreased adipocyte size. These data strongly suggest that PPARG play a major role in the metabolic adaptations to western diet characterized by an excessive amount of saturated fat. Considering the metabolic properties of the two other PPAR isotypes, D and J, it is likely that the three PPAR isotypes have complementary effects in the pathophysiology of obesity and metabolic syndrome. Future therapeutical perspectives in this field should consider combined treatment, adding G agonists (for all that their safety will be established) to the already available D and J agonists.
PPAR delta : un récepteur nucléaire mal connu
Key-words: PPAR · Diabetes Atherosclerosis · Lipoprotein.
·
Metabolic
syndrome
·
Les récepteurs activés par les proliférateurs de peroxisomes (PPAR) relaient un certain nombre d’effets transcriptionnels des acides gras et contrôlent de nombreuses fonctions physiologiques, notamment en matière de développement et de métabolisme. On en connaît trois isoformes, D, J et E/G. Les rôles de PPAR D et J sont maintenant bien connus, surtout depuis la commercialisation de leurs agonistes pharmacologiques, respectivement les normolipémiants de la classe des fibrates, et les antidiabétiques de la classe des thiazolidinediones. Cependant, les fonctions de PPARG sont encore incomplètement élucidées, bien que des données récentes soulignent son rôle dans la régulation de l’oxydation des acides gras dans différents tissus, notamment le muscle squelettique et le tissu adipeux. En effet, la surexpression de PPARG chez la souris transgénique accroît la capacité oxydative du muscle. Cela s’accompagne d’une redistribution du flux d’acides gras, redirigé du tissu adipeux vers le muscle. Ces résultats suggèrent fortement que PPARG joue un rôle important dans les adaptations métaboliques de l’organisme à une alimentation de type occidental, caractérisée par un apport excessif de graisses saturées. Si l’on prend en compte les propriétés métaboliques des deux autres isotypes D et J, il est probable que les trois isotypes des PPAR ont des actions complémentaires dans la physiopathologie de l’obésité et du syndrome métabolique. Le traitement pharmacologique futur de ces pathologies devra comprendre un traitement combiné « polyPPAR », en rajoutant un agoniste delta (pour autant que sa sécurité d’emploi soit établie) aux agonistes alpha et gamma déjà disponibles.
.
Fredenrich A, Grimaldi PA PPAR delta: an uncompletely known nuclear receptor Diabetes Metab 2005,31,23-27
1
2
INSERM, U 636, Centre de Biochimie, UFR Sciences, Parc Valrose, Université de Nice-Sophia-Antipolis, Nice, F-06108 France CHU de Nice, Hôpital Pasteur, Service de Diabétologie-Endocrinologie, Nice Cedex 1, F-06002 France.
Mots-clés : PPAR · Diabète Athérosclérose · Lipoprotéine.
·
Syndrome
métabolique
·
Address correspondence and reprint requests to: A Fredenrich. Service de Diabétologie-Endocrinologie, Hôpital Pasteur, 06002 Nice Cedex 1, France. [email protected] Received: September 20th, 2004; revised: November 17th, 2004
Diabetes Metab 2005,31,23-27 • © 2005 Masson, all rights reserved
23
A Fredenrich et al.
P
eroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. Ligand activation heterodimerizes PPARs with another nuclear receptor, the 9-cis retinoic acid receptor, and this dimer acts on transcription of some target genes after binding to specific peroxisome proliferator response elements [1]. Three PPAR isotypes have been described, D, EG, and J, which differ by their target tissue and physiological properties [2]. PPARD is mainly found in liver. It is activated by polyunsatured fatty acids and leukotriene B4, and this activation increases fatty acid catabolism. This explains the lipid-normalizing effect of fibrates, which are specific pharmacological activators. PPAR J is expressed mainly in adipocytes, and is activated by prostaglandins and by thiazolidinediones (glitazones), a recently available class of insulin-sensitizing drugs. Functions of the third member of PPAR family, PPARG, remained elusive until recently. Recent data using specific agonists and appropriate animal models have clarified its metabolic roles and enhanced the potential role of this receptor as a pharmacological target [3].
PPARG and regulation of lipid metabolism PPARG has an ubiquitous tissue distribution : it is expressed in white adipose tissue, heart, muscle, intestine, placenta and macrophages [4]. It is activated by unsaturated or saturated long-chain fatty acids [5], by prostacyclin, by retinoic acid, and some eicosanoids [6] (Fig 1). Pharmacological agonists have been synthesized, especially GW 501516 and L 165041, which activate PPARG with a much higher selectivity compared to other PPAR isotypes. A pivotal role of the synthetic specific agonist, GW 501516, has been evidenced by Oliver et al. In insulin-resistant obese rhesus monkeys, administration of GW 501516 during 4 weeks increased HDL-cholesterol, decreased LDLcholesterol, triglycerides and fasting plasma insulin, and lowered the levels of small and dense LDL [7]. A major question was to identify the tissue and the mechanisms of action involved in these results. Administration of GW 501516 for 3 to 4 weeks in wild-type mice induces fatty acid E-oxidation in skeletal muscle [8]. Further evidence Abbreviations APOA1 : APOB : APOCIII : BCL-6 : HDL : LDL : NEFA : PGC-1 : PPAR : TG : VLDL :
24
Apolipoprotein A1 Apolipoprotein B Apolipoprotein CIII B-cell lymphoma gene 6 High-density lipoprotein Low-density lipoprotein Non-esterified fatty acids Peroxisome proliferator-activated receptor gamma coactivator-1 Peroxisome proliferator-activated receptor Triglycerides Very low-density lipoprotein
Diabetes Metab 2005,31,23-27 • www.e2med.com/dm
came from the utilization of transgenic murine models, which allowed tissue-specific overexpression of PPARG. A ligand-independent active form of the nuclear receptor has been shown to be specifically expressed in white and brown adipose tissues, and it upregulated expression of genes involved in fatty acid catabolism and energy uncoupling in adipose cells [9]. This is accompanied by a decrease of adiposity in mice fed either with standard or high-fat diet. Using a transgenic mice model constructed with a Cre-Lox recombination technique, we showed that overexpression of PPARG in skeletal muscle leads to a major increase of metabolic oxidative capability characterized by an elevated proportion of oxidative myofibers (type 2a) and elevation of oxidative enzymatic activities, accompanied by a dramatic reduction of body fat due to a decrease of adipocyte diameter [10]. The global result was a muscle remodelling characterized by an increase in the total number of oxidative fibers which is quite similar to that promoted by long-term moderate exercise. To challenge this hypothesis, we investigated the effects of endurance exercise on the PPARG protein content in muscle of wild-type mice, and we showed that it was increased by 2.6 fold in tibialis anterior muscle after 6 weeks of training. Taken together, these results suggest that PPARG is directly involved in the muscle remodelling observed during endurance exercise, and possibly in the beneficial effects of exercise on metabolic syndrome. Conversion of type 2 muscle fibers into type 1-like fibers has been also observed in mice overexpressing PPARJ-coactivator 1 (PGC-1) [11], but overexpression of PGC-1 is characterized by a complete conversion of fast-twitch into slowtwitch fibers, while overexpression of PPARG does not promote appearance of actual type 1 fibers in tibialis anterior or plantaris muscles. Mechanism of actions involves a redistribution of the non-esterified fatty acids (NEFA) flux : the increased oxidative capability draws the NEFA flux towards the muscle to be preferentially oxidized, rather than be stored in adipocytes. This leads to a decrease in adipocyte size, enhanced lipolysis and increased secretion of the main anti-atherogenic and insulin-sensitizing cytokine, adiponectin (Fig 3).
PPARG and atherosclerosis A growing body of evidence suggests that PPARG could be involved in the pathophysiology of atherosclerosis due to its pivotal role in lipid metabolism. Implication of activation of the receptor in this field has been demonstrated by the previously cited study of Oliver et al. in obese rhesus monkeys [7]. Moreover some recent publications have focused on the possible link between polymorphisms of the PPARG gene and the plasma concentrations of HDL- and LDL-cholesterol in various human populations. First, Skogsberg et al. showed that among four poly-
PPAR delta: an uncompletely known nuclear receptor
Adipose, Heart, Muscle Intestine, Placenta, M a c r o p h a g es
LCFA PGI2 Retinoic Acid
R E G UL AT I O NS O F DE VE L O P M E NT : - C on t r ol b y L C F A of p r ea d ip ocyt es p r olifer a t ion a n d d iffer en cia t ion . - I m p la n t a t ion of e m b r yo . - C o n t r ol o f en t e r oc yt e s p r ol if er a t i on . - D iff e r en c ia t io n a n d p r o l ife r a t io n o f k e r a t in o cy t e s .
PPARδ
GW 501516 L165041
METABOLIC REGULATIONS: Treatment with PPARδ agonist normalizes plasma triglycerides, insulinemia and HDL-cholesterol. (Oliver et al, ref. 7)
13-S-HODE
Mechanism of action and target tissue (s)?
Figure 1 Physiological roles of PPAR G. Different natural and synthetic ligands are known to activate this ubiquituous receptor. It is mainly involved in: a) regulation of development b) some pivotal metabolic regulations, as evidenced by Oliver et al. [7]. Exact mechanism and target tissues of this metabolic action remain partially unknown. LCFA: long chain fatty acid; PGI2: prostacyclin; HODE: hydroxyoctadecadienoic acid.
Ex er c is e
PPAR δ + Agonists
FFA Dec reas e of adipocyte size
Lipolysis
Increased number of oxidative fibers and oxidative metabolism
+ +
morphisms (-409C/T, +73C/T, +255A/G, +294T/C), homozygote individuals for the rare C allele at the +294 locus had a higher plasma LDL-concentration than homozygotes for the common T allele [12]. Moreover, the same author, in individuals sampled from the prospective primary prevention West of Scotland Coronary Prevention Study, showed that individuals carrying the +294C allele had significantly lower plasma HDL-cholesterol concentrations compared to the carriers of the T-allele. Homozygous carriers of the C-allele also had a trend towards higher risk of coronary heart disease compared to the homozygous carriers of the T-allele [13]. Finally, Chen et al., in 372 individuals sampled from the Lipoprotein and
Adipocytokines
Figure 2 Integrated overview of the connecting action of PPARG between muscle and adipose tissue. Activation of PPARG either by ligands or exercise increases the amount of oxidative fibers in the muscle. This leads to a redistribution of the NEFA flux, then preferably directed to the muscle to be oxidized rather than stored by adipocytes. The resulting decrease in adipocyte size promotes secretion of the main anti-atherogenic cytokine, adiponectin. NEFA: nonesterified fatty acids.
Coronary Atherosclerosis Study, showed that PPARG haplotypes were independent determinants of plasma levels of triglycerides, apoB and apoCIII, of mean number of coronary lesions, and of changes in triglyceride and apoCIII levels in response to a normolipidemic drug, fluvastatin [14]. Nevertheless, the effective role of PPARG in atherosclerosis is still difficult to assess, as recent data have established both antiatherogenic and proatherogenic properties of the receptor. PPARG seems to act as a VLDL sensor in macrophages and is therefore involved in lipid accumulation in atherosclerotic plaques [15]. Lee et al. have shown very recently that the role of PPARG in inflammation depends whether a ligand is bound or not to Diabetes Metab 2005,31,23-27 • © 2005 Masson, all rights reserved
25
A Fredenrich et al.
DIETARY LIPIDS NORMAL SEDENTARITY
METABOLIC SYNDROME
PPAR Agonists PPARγ / TZDs : Recruitment of new adipocytes PPARα / Fibrates : Hepatic oxydation of NEFAS Lipoprotein secretion and metabolism
PPARδ /Agonists Muscle oxydation of NEFAS
the receptor. Binding leads to the release of B-cell lymphoma gene 6 (BCL-6), which is a repressor of inflammatory response; this results in decreased expression of inflammatory cytokine genes, reduced inflammation and subsequently possible decrease of atherosclerosis. Conversely, in the absence of ligand, BCL-6 remains bound to PPARG, and the inflammatory process is no longer repressed [16]. These results show that the role of PPARG in atherosclerosis is perhaps more ambiguous than previously thought.
Integrated roles of PPARs in the pathophysiology and treatment of metabolic syndrome The metabolic syndrome is characterized by the simultaneous occurrence of at least three out of the five following metabolic disorders : hypertension, visceral adiposity, hyperglycemia, hypertriglyceridemia, low HDL-cholesterol levels [17]. The common soil of this cluster of cardio-vascular risk factors is an insulin resistance state. Each PPAR isotype can play a role in this syndrome [18]. The central role of PPARD has yet been demonstrated [19]. Its activation increases the uptake and catabolism of fatty acids, leading to a limited TG and VLDL production by the liver. It also inhibits the hepatic synthesis of ApoCIII, which is an inhibitor of lipoprotein lipase activity and remnant catabolism. Moreover, in reverse cholesterol transport from peripheral cells to liver, activation of PPARD induces synthesis of ApoA1 [20] and expression of the hepatic receptor SRB1 [21]. These changes 26
Diabetes Metab 2005,31,23-27 • www.e2med.com/dm
Figure 3 Complementary effects of the three PPAR isotypes in the treatment of the metabolic syndrome.Thiazolidinediones (glitazones) and fibrates are commercially available, in the pharmacological treatment of respectively type 2 diabetes (especially if insulin resistance is predominant) and dyslipidemia (especially when hypertriglyceridemia and/or low HDL-cholesterol are present). Concerning PPARG activation, besides physical exercise, synthetic ligands are now under clinical development. TZD: thiazolidinediones.
are evidenced by the use of fibrates, which are specific pharmacological activators, leading to a decrease of plasma triglycerides concentration, and an increase of HDL-cholesterol plasma level. PPARJ plays also a major role in insulin resistance, by controlling adipogenesis [22]. Activation of PPARJ induces a remodelling of adipose tissue, with recruitment of new metabolically active adipocytes, promoting the secretion of an anti-atherogenic and insulin-sensitizing cytokine, adiponectin. A recently available class of pharmacological agonists of PPARJ, glitazones, displays not only hypoglycemic properties, but also a panel of pleiotropic actions, such as a decrease of C-reactive protein plasma level and expression of adhesion molecules and metalloproteinases, inhibition of proliferation of smooth muscle cells and secretion of numerous proatherogenic cytokines such as tumor-necrosis factor D and interleukin 6 [23]. Furthermore, glitazones increase adiponectin gene expression in adipose tissue and therefore plasma levels of this cytokine [24]. Antidiabetic actions of glitazones might also involve plasma NEFA-lowering effect through increased glycerol-3-phosphate availability for TG synthesis, by upregulation of phosphoenolpyruvate carboxykinase and glycerol kinase [25, 26]. Finally, the third isotype, PPARG, seems to be greatly involved in the field. We have seen that utilization of an agonist of PPARG is able in mice and monkeys to reverse the main features of the metabolic syndrome. Although level of experimental evidence is still restrained to animal model, clinical trials have been initiated in humans, and will provide important data concerning efficiency, tolerance and safety of the agonist.
PPAR delta: an uncompletely known nuclear receptor
Taken together, these data suggest that combined use of agonists of the three isotypes of PPARs (eventually combined in a « Poly-PPAR-Pill », PPP) could target the whole body of pathophysiological features of the metabolic syndrome [27, 28] ( 3).
Acknowledgements – A. Fredenrich is supported by a “Contrat d’Objectif CHU-INSERM”.
14.
15.
16.
References 17. 1.
Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology, 2003, 144, 2201-7.
2.
Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev, 1999, 20, 649-88.
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Fredenrich A, Grimaldi PA. Roles of peroxisome proliferator-activated receptor G in skeletal muscle function and adaptation. Curr Op Clin Nutr Metab Care, 2004, 7, 377-81.
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Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of PPARs: tissue distribution of PPAR-alpha, -beta and gamma in the adult rat. Endocrinology, 1996, 137, 354-66.
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Amri EZ, Bonino F, Ailhaud G, Abumrad NA, Grimaldi PA. 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.
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Hertz R, Berman I, Keppler D, Bar-Tana J. Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome proliferator-activated receptor (PPAR). Eur J Biochem, 1996, 235, 242-7.
7.
Oliver WR, Shenk JL, Snaith MR, et al. A selective peroxisome proliferator-activated receptor d agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA, 2001, 98, 5306-11.
8.
Tanaka T, Yamamoto J, Iwasaki S, et al. 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.
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Wang YX, Lee CH, Tiep S, et al. Peroxisome proliferator-activated receptor G activates fat metabolism to prevent obesity. Cell, 2003, 113, 159-70.
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10. Luquet S, Lopez-Soriano J, Holst D, et al. Peroxisome proliferatoractivated receptor G controls muscle development and oxidative capability. Faseb J, 2003, 17, 2299-301.
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11. Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1a drives the formation of slow-twitch muscle fibres. Nature, 2002, 418, 797-801.
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12. Skogsberg J, Kannisto K, Cassel TN, Hamsten A, Eriksson P, Ehrenborg E. Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men. Arterioscler Thromb Vasc Biol, 2003, 23, 637-43. 13. Skogsberg J, McMahon AD, Karpe F, Hamsten A, Packard CJ, Ehrenborg E. Peroxisome proliferator activated receptor G genotype
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in relation to cardiovascular risk factors and risk of coronary heart disease in hypercholesterolemic men. J Int Med, 2003, 254, 597-604. Chen S, Tsybouleva N, Ballantyne CM, Gotto AM Jr, Marian AJ. Effects of PPARD, J and G haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the Lipoprotein Coronary Atherosclerosis Study. Pharmacogenetics, 2004, 14, 61-71. Chawla A, Lee CH, Barak Y, et al. PPARG is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci USA, 2003, 100, 1268-73. Lee CH, Chawla A, Urbiztondo N, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARG. Science, 2003, 302, 453-7. Expert panel on detection, evaluation and treatment of high blood cholesterol in adults. Executive summary of the third report on the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult treatment Panel III). JAMA, 2001, 285, 2486-2497. Barbier O, Pineda Torra I, Duguay Y, et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol, 2002, 22, 717-26. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998, 98, 2088-93. Vu-Dac N, Schoonjans K, Laine B, Fruchart JC, Auwerx J, Staels B. Negative regulation of the human apolipoprotein A-1 promoter by fibrates can be attenuated by the interaction of the peroxisome proliferator-activated recpetor with its response element. J Biol Chem, 1994, 269, 31012-8. Chinetti G, Gbaguidi FG, Griglio S, et al. CLA-1/SR-B1 is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome prloliferator-activated receptors. Circulation, 2000, 101, 2411-7. Grimaldi PA. The roles of PPARs in adipocyte differenciation. Prog Lipid Res, 2001, 40, 269-81. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med, 2001, 134, 61-71. Yu JG, Javorschi S, Hevener AL, et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes, 2002, 51, 2968-74. Tordjman J, Khazen W, Antoine B, et al. Regulation of glyceroneogenesis and phosphoenolpyruvate carboxykinase by fatty acids, retinoic acids and thiazolidinediones: potential relevance to type 2 diabetes. Biochimie, 2004, 85, 1213-8. Rangwala SM, Lazar MA. Peroxisome proliferator-activated receptor J in diabetes and metabolism. Trends Pharmacol Sci, 2004, 25, 331-6. Lewis MC, Wilson JG, Ignar DM, Oliver WR Jr. The effects of PPARD, G and PPARpanTM agonists on diet-induced obesity in fatfed AKR mice. Diabetes, 2004, 53, suppl 2, A 134. Ortmeyer HK, Collins CA, Minnick DT, et al. PPARpanTM agonist treatment improves lipid utilization via tissue-specific effects on skeletal muscle and adipose tissue lipoprotein lipase activity in obese monkeys. Diabetes, 2004, 53, suppl 2, A 159.
Diabetes Metab 2005,31,23-27 • © 2005 Masson, all rights reserved
27
R E V I E W
PPAR delta: an uncompletely known nuclear receptor A Fredenrich1,2, PA Grimaldi1
SUMMARY
RÉSUMÉ
Peroxisome proliferator-activated receptors (PPAR) mediate some of the transcriptional effects of fatty acids and control many physiological functions, especially in the field of development and metabolism. Three isotypes are known, D, J, and E/G. Roles of PPAR D and PPARJ are now quite well-known, particularly since their pharmacologic ligands have been marketed, respectively the lipid-normalizing class of fibrates and the antidiabetic class of thiazolidinediones (glitazones). However, functions of PPARG are uncompletely known to date, but some recent data enlight its role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue. Overexpression of PPARG using a transgenic murine model promotes an increase of muscle oxidative capability. This is accompanied by a redistribution of fatty acid flux, redirected from adipose tissue towards skeletal muscle. Finally, adipose mass is reduced, due to a decreased adipocyte size. These data strongly suggest that PPARG play a major role in the metabolic adaptations to western diet characterized by an excessive amount of saturated fat. Considering the metabolic properties of the two other PPAR isotypes, D and J, it is likely that the three PPAR isotypes have complementary effects in the pathophysiology of obesity and metabolic syndrome. Future therapeutical perspectives in this field should consider combined treatment, adding G agonists (for all that their safety will be established) to the already available D and J agonists.
PPAR delta : un récepteur nucléaire mal connu
Key-words: PPAR · Diabetes Atherosclerosis · Lipoprotein.
·
Metabolic
syndrome
·
Les récepteurs activés par les proliférateurs de peroxisomes (PPAR) relaient un certain nombre d’effets transcriptionnels des acides gras et contrôlent de nombreuses fonctions physiologiques, notamment en matière de développement et de métabolisme. On en connaît trois isoformes, D, J et E/G. Les rôles de PPAR D et J sont maintenant bien connus, surtout depuis la commercialisation de leurs agonistes pharmacologiques, respectivement les normolipémiants de la classe des fibrates, et les antidiabétiques de la classe des thiazolidinediones. Cependant, les fonctions de PPARG sont encore incomplètement élucidées, bien que des données récentes soulignent son rôle dans la régulation de l’oxydation des acides gras dans différents tissus, notamment le muscle squelettique et le tissu adipeux. En effet, la surexpression de PPARG chez la souris transgénique accroît la capacité oxydative du muscle. Cela s’accompagne d’une redistribution du flux d’acides gras, redirigé du tissu adipeux vers le muscle. Ces résultats suggèrent fortement que PPARG joue un rôle important dans les adaptations métaboliques de l’organisme à une alimentation de type occidental, caractérisée par un apport excessif de graisses saturées. Si l’on prend en compte les propriétés métaboliques des deux autres isotypes D et J, il est probable que les trois isotypes des PPAR ont des actions complémentaires dans la physiopathologie de l’obésité et du syndrome métabolique. Le traitement pharmacologique futur de ces pathologies devra comprendre un traitement combiné « polyPPAR », en rajoutant un agoniste delta (pour autant que sa sécurité d’emploi soit établie) aux agonistes alpha et gamma déjà disponibles.
.
Fredenrich A, Grimaldi PA PPAR delta: an uncompletely known nuclear receptor Diabetes Metab 2005,31,23-27
1
2
INSERM, U 636, Centre de Biochimie, UFR Sciences, Parc Valrose, Université de Nice-Sophia-Antipolis, Nice, F-06108 France CHU de Nice, Hôpital Pasteur, Service de Diabétologie-Endocrinologie, Nice Cedex 1, F-06002 France.
Mots-clés : PPAR · Diabète Athérosclérose · Lipoprotéine.
·
Syndrome
métabolique
·
Address correspondence and reprint requests to: A Fredenrich. Service de Diabétologie-Endocrinologie, Hôpital Pasteur, 06002 Nice Cedex 1, France. [email protected] Received: September 20th, 2004; revised: November 17th, 2004
Diabetes Metab 2005,31,23-27 • © 2005 Masson, all rights reserved
23
A Fredenrich et al.
P
eroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. Ligand activation heterodimerizes PPARs with another nuclear receptor, the 9-cis retinoic acid receptor, and this dimer acts on transcription of some target genes after binding to specific peroxisome proliferator response elements [1]. Three PPAR isotypes have been described, D, EG, and J, which differ by their target tissue and physiological properties [2]. PPARD is mainly found in liver. It is activated by polyunsatured fatty acids and leukotriene B4, and this activation increases fatty acid catabolism. This explains the lipid-normalizing effect of fibrates, which are specific pharmacological activators. PPAR J is expressed mainly in adipocytes, and is activated by prostaglandins and by thiazolidinediones (glitazones), a recently available class of insulin-sensitizing drugs. Functions of the third member of PPAR family, PPARG, remained elusive until recently. Recent data using specific agonists and appropriate animal models have clarified its metabolic roles and enhanced the potential role of this receptor as a pharmacological target [3].
PPARG and regulation of lipid metabolism PPARG has an ubiquitous tissue distribution : it is expressed in white adipose tissue, heart, muscle, intestine, placenta and macrophages [4]. It is activated by unsaturated or saturated long-chain fatty acids [5], by prostacyclin, by retinoic acid, and some eicosanoids [6] (Fig 1). Pharmacological agonists have been synthesized, especially GW 501516 and L 165041, which activate PPARG with a much higher selectivity compared to other PPAR isotypes. A pivotal role of the synthetic specific agonist, GW 501516, has been evidenced by Oliver et al. In insulin-resistant obese rhesus monkeys, administration of GW 501516 during 4 weeks increased HDL-cholesterol, decreased LDLcholesterol, triglycerides and fasting plasma insulin, and lowered the levels of small and dense LDL [7]. A major question was to identify the tissue and the mechanisms of action involved in these results. Administration of GW 501516 for 3 to 4 weeks in wild-type mice induces fatty acid E-oxidation in skeletal muscle [8]. Further evidence Abbreviations APOA1 : APOB : APOCIII : BCL-6 : HDL : LDL : NEFA : PGC-1 : PPAR : TG : VLDL :
24
Apolipoprotein A1 Apolipoprotein B Apolipoprotein CIII B-cell lymphoma gene 6 High-density lipoprotein Low-density lipoprotein Non-esterified fatty acids Peroxisome proliferator-activated receptor gamma coactivator-1 Peroxisome proliferator-activated receptor Triglycerides Very low-density lipoprotein
Diabetes Metab 2005,31,23-27 • www.e2med.com/dm
came from the utilization of transgenic murine models, which allowed tissue-specific overexpression of PPARG. A ligand-independent active form of the nuclear receptor has been shown to be specifically expressed in white and brown adipose tissues, and it upregulated expression of genes involved in fatty acid catabolism and energy uncoupling in adipose cells [9]. This is accompanied by a decrease of adiposity in mice fed either with standard or high-fat diet. Using a transgenic mice model constructed with a Cre-Lox recombination technique, we showed that overexpression of PPARG in skeletal muscle leads to a major increase of metabolic oxidative capability characterized by an elevated proportion of oxidative myofibers (type 2a) and elevation of oxidative enzymatic activities, accompanied by a dramatic reduction of body fat due to a decrease of adipocyte diameter [10]. The global result was a muscle remodelling characterized by an increase in the total number of oxidative fibers which is quite similar to that promoted by long-term moderate exercise. To challenge this hypothesis, we investigated the effects of endurance exercise on the PPARG protein content in muscle of wild-type mice, and we showed that it was increased by 2.6 fold in tibialis anterior muscle after 6 weeks of training. Taken together, these results suggest that PPARG is directly involved in the muscle remodelling observed during endurance exercise, and possibly in the beneficial effects of exercise on metabolic syndrome. Conversion of type 2 muscle fibers into type 1-like fibers has been also observed in mice overexpressing PPARJ-coactivator 1 (PGC-1) [11], but overexpression of PGC-1 is characterized by a complete conversion of fast-twitch into slowtwitch fibers, while overexpression of PPARG does not promote appearance of actual type 1 fibers in tibialis anterior or plantaris muscles. Mechanism of actions involves a redistribution of the non-esterified fatty acids (NEFA) flux : the increased oxidative capability draws the NEFA flux towards the muscle to be preferentially oxidized, rather than be stored in adipocytes. This leads to a decrease in adipocyte size, enhanced lipolysis and increased secretion of the main anti-atherogenic and insulin-sensitizing cytokine, adiponectin (Fig 3).
PPARG and atherosclerosis A growing body of evidence suggests that PPARG could be involved in the pathophysiology of atherosclerosis due to its pivotal role in lipid metabolism. Implication of activation of the receptor in this field has been demonstrated by the previously cited study of Oliver et al. in obese rhesus monkeys [7]. Moreover some recent publications have focused on the possible link between polymorphisms of the PPARG gene and the plasma concentrations of HDL- and LDL-cholesterol in various human populations. First, Skogsberg et al. showed that among four poly-
PPAR delta: an uncompletely known nuclear receptor
Adipose, Heart, Muscle Intestine, Placenta, M a c r o p h a g es
LCFA PGI2 Retinoic Acid
R E G UL AT I O NS O F DE VE L O P M E NT : - C on t r ol b y L C F A of p r ea d ip ocyt es p r olifer a t ion a n d d iffer en cia t ion . - I m p la n t a t ion of e m b r yo . - C o n t r ol o f en t e r oc yt e s p r ol if er a t i on . - D iff e r en c ia t io n a n d p r o l ife r a t io n o f k e r a t in o cy t e s .
PPARδ
GW 501516 L165041
METABOLIC REGULATIONS: Treatment with PPARδ agonist normalizes plasma triglycerides, insulinemia and HDL-cholesterol. (Oliver et al, ref. 7)
13-S-HODE
Mechanism of action and target tissue (s)?
Figure 1 Physiological roles of PPAR G. Different natural and synthetic ligands are known to activate this ubiquituous receptor. It is mainly involved in: a) regulation of development b) some pivotal metabolic regulations, as evidenced by Oliver et al. [7]. Exact mechanism and target tissues of this metabolic action remain partially unknown. LCFA: long chain fatty acid; PGI2: prostacyclin; HODE: hydroxyoctadecadienoic acid.
Ex er c is e
PPAR δ + Agonists
FFA Dec reas e of adipocyte size
Lipolysis
Increased number of oxidative fibers and oxidative metabolism
+ +
morphisms (-409C/T, +73C/T, +255A/G, +294T/C), homozygote individuals for the rare C allele at the +294 locus had a higher plasma LDL-concentration than homozygotes for the common T allele [12]. Moreover, the same author, in individuals sampled from the prospective primary prevention West of Scotland Coronary Prevention Study, showed that individuals carrying the +294C allele had significantly lower plasma HDL-cholesterol concentrations compared to the carriers of the T-allele. Homozygous carriers of the C-allele also had a trend towards higher risk of coronary heart disease compared to the homozygous carriers of the T-allele [13]. Finally, Chen et al., in 372 individuals sampled from the Lipoprotein and
Adipocytokines
Figure 2 Integrated overview of the connecting action of PPARG between muscle and adipose tissue. Activation of PPARG either by ligands or exercise increases the amount of oxidative fibers in the muscle. This leads to a redistribution of the NEFA flux, then preferably directed to the muscle to be oxidized rather than stored by adipocytes. The resulting decrease in adipocyte size promotes secretion of the main anti-atherogenic cytokine, adiponectin. NEFA: nonesterified fatty acids.
Coronary Atherosclerosis Study, showed that PPARG haplotypes were independent determinants of plasma levels of triglycerides, apoB and apoCIII, of mean number of coronary lesions, and of changes in triglyceride and apoCIII levels in response to a normolipidemic drug, fluvastatin [14]. Nevertheless, the effective role of PPARG in atherosclerosis is still difficult to assess, as recent data have established both antiatherogenic and proatherogenic properties of the receptor. PPARG seems to act as a VLDL sensor in macrophages and is therefore involved in lipid accumulation in atherosclerotic plaques [15]. Lee et al. have shown very recently that the role of PPARG in inflammation depends whether a ligand is bound or not to Diabetes Metab 2005,31,23-27 • © 2005 Masson, all rights reserved
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A Fredenrich et al.
DIETARY LIPIDS NORMAL SEDENTARITY
METABOLIC SYNDROME
PPAR Agonists PPARγ / TZDs : Recruitment of new adipocytes PPARα / Fibrates : Hepatic oxydation of NEFAS Lipoprotein secretion and metabolism
PPARδ /Agonists Muscle oxydation of NEFAS
the receptor. Binding leads to the release of B-cell lymphoma gene 6 (BCL-6), which is a repressor of inflammatory response; this results in decreased expression of inflammatory cytokine genes, reduced inflammation and subsequently possible decrease of atherosclerosis. Conversely, in the absence of ligand, BCL-6 remains bound to PPARG, and the inflammatory process is no longer repressed [16]. These results show that the role of PPARG in atherosclerosis is perhaps more ambiguous than previously thought.
Integrated roles of PPARs in the pathophysiology and treatment of metabolic syndrome The metabolic syndrome is characterized by the simultaneous occurrence of at least three out of the five following metabolic disorders : hypertension, visceral adiposity, hyperglycemia, hypertriglyceridemia, low HDL-cholesterol levels [17]. The common soil of this cluster of cardio-vascular risk factors is an insulin resistance state. Each PPAR isotype can play a role in this syndrome [18]. The central role of PPARD has yet been demonstrated [19]. Its activation increases the uptake and catabolism of fatty acids, leading to a limited TG and VLDL production by the liver. It also inhibits the hepatic synthesis of ApoCIII, which is an inhibitor of lipoprotein lipase activity and remnant catabolism. Moreover, in reverse cholesterol transport from peripheral cells to liver, activation of PPARD induces synthesis of ApoA1 [20] and expression of the hepatic receptor SRB1 [21]. These changes 26
Diabetes Metab 2005,31,23-27 • www.e2med.com/dm
Figure 3 Complementary effects of the three PPAR isotypes in the treatment of the metabolic syndrome.Thiazolidinediones (glitazones) and fibrates are commercially available, in the pharmacological treatment of respectively type 2 diabetes (especially if insulin resistance is predominant) and dyslipidemia (especially when hypertriglyceridemia and/or low HDL-cholesterol are present). Concerning PPARG activation, besides physical exercise, synthetic ligands are now under clinical development. TZD: thiazolidinediones.
are evidenced by the use of fibrates, which are specific pharmacological activators, leading to a decrease of plasma triglycerides concentration, and an increase of HDL-cholesterol plasma level. PPARJ plays also a major role in insulin resistance, by controlling adipogenesis [22]. Activation of PPARJ induces a remodelling of adipose tissue, with recruitment of new metabolically active adipocytes, promoting the secretion of an anti-atherogenic and insulin-sensitizing cytokine, adiponectin. A recently available class of pharmacological agonists of PPARJ, glitazones, displays not only hypoglycemic properties, but also a panel of pleiotropic actions, such as a decrease of C-reactive protein plasma level and expression of adhesion molecules and metalloproteinases, inhibition of proliferation of smooth muscle cells and secretion of numerous proatherogenic cytokines such as tumor-necrosis factor D and interleukin 6 [23]. Furthermore, glitazones increase adiponectin gene expression in adipose tissue and therefore plasma levels of this cytokine [24]. Antidiabetic actions of glitazones might also involve plasma NEFA-lowering effect through increased glycerol-3-phosphate availability for TG synthesis, by upregulation of phosphoenolpyruvate carboxykinase and glycerol kinase [25, 26]. Finally, the third isotype, PPARG, seems to be greatly involved in the field. We have seen that utilization of an agonist of PPARG is able in mice and monkeys to reverse the main features of the metabolic syndrome. Although level of experimental evidence is still restrained to animal model, clinical trials have been initiated in humans, and will provide important data concerning efficiency, tolerance and safety of the agonist.
PPAR delta: an uncompletely known nuclear receptor
Taken together, these data suggest that combined use of agonists of the three isotypes of PPARs (eventually combined in a « Poly-PPAR-Pill », PPP) could target the whole body of pathophysiological features of the metabolic syndrome [27, 28] ( 3).
Acknowledgements – A. Fredenrich is supported by a “Contrat d’Objectif CHU-INSERM”.
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Diabetes Metab 2005,31,23-27 • © 2005 Masson, all rights reserved
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