Peroxisome proliferator–activated receptor γ ligands and atherosclerosis: ending the heartache
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TLDR
Several lines of evidence have now converged to identify the peroxisome proliferator–activated receptor γ (PPARγ) as the relevant molecular target of these compounds (4).Abstract:
One of the great ironies of the present-day industrialized world is serious disease and death brought about by too much rich food and too little physical exertion. The incidence of obesity has increased to the point that one in two American adults is now considered overweight (1). Pathologies linked to obesity, such as type 2 diabetes, hypertension, and cardiovascular disorders, are also increasingly prevalent in our society.
The tight linkage of obesity, insulin resistance (and frank diabetes), dyslipidemia, and hypertension has been widely observed and has been dignified with a label – syndrome X, or the metabolic syndrome (2). The exact pathogenic relationships between the component conditions of the metabolic syndrome are complex and incompletely understood, despite significant and ongoing efforts to identify susceptibility genes in human populations and animal models. The convergence of these conditions in the metabolic syndrome is not an area isolated to mere academic interest: Coronary and peripheral vascular disease leading to myocardial infarction and stroke is the unhappy fate of many affected individuals.
In an ideal world, the metabolic syndrome would be treated by diet and exercise, leading to weight loss. Even relatively modest degrees of weight loss have been shown to improve markers of the metabolic syndrome, such as blood pressure, serum cholesterol, and insulin levels. Unfortunately, most patients find the necessary dietary and exercise regimens to be difficult. Even if the difficulty is surmounted, they find that their bodies resist any deviation from the “set-point” of their elevated weight. Much emphasis, therefore, has been placed on treating the component conditions of the metabolic syndrome pharmacologically. Indeed, these efforts have been successful, and new medications for hypertension and dyslipidemia are now available that can reduce morbidity and mortality from cardiovascular disease in these patients.
The treatment of insulin resistance and diabetes has until recently been restricted to the administration of exogenous insulin or to sulfonylureas, which promote the release of endogenous insulin. Although effective at reducing serum glucose levels in diabetic patients, neither of these agents addresses the underlying insulin resistance at the core of the metabolic syndrome. In the last five years, however, metformin became available in the US. Metformin reduces insulin resistance primarily in the liver, although its precise molecular targets are not known. Unfortunately, the use of metformin in patients with significant renal, hepatic, or cardiac impairment can lead to life-threatening lactic acidosis, reducing the utility of this agent in many people with diabetes (3).
It was with considerable excitement, therefore, that the thiazolidinedione (TZD) drugs were introduced into the US market in the last five years. Like metformin, these antidiabetic agents, such as troglitazone (Rezulin™), rosiglitazone (Avandia™), and pioglitazone (Actos™), were originally developed without knowledge of their mechanism of action. Several lines of evidence, however, have now converged to identify the peroxisome proliferator–activated receptor γ (PPARγ) as the relevant molecular target of these compounds (4). Perhaps most convincing is the fact that non-TZD synthetic compounds isolated solely on the basis of binding to PPARγ, a ligand-activated transcriptional regulator, exert antidiabetic effects similar to those of the TZDs (5).
As discussed by Olefsky (6) and others in the recent JCI Perspective series on insulin resistance, TZDs reduce insulin resistance and improve glucose homeostasis in diabetic rodents and humans. Nevertheless, concerns remain about possible deleterious side effects of these drugs. Troglitazone, the first TZD approved, was shown to have hepatotoxic effects in some patients during postmarketing analysis (7). Unfortunately, this reaction was severe enough in a few patients to cause death or a requirement for liver transplantation, leading to the withdrawal of this drug from the US market. Thus far, monitoring of patients taking rosiglitazone and pioglitazone has not revealed significant hepatotoxicity suggesting that this undesired effect may be idiosyncratic to troglitazone and not related to the activation of PPARγ per se. A more precise understanding of the spectrum of side effects of rosiglitazone and pioglitazone must await more studies in larger numbers of patients.
One complicating feature in the use of PPARγ agonists is that the precise tissue targets relevant to metabolic disease are not fully understood. PPARγ is expressed at its highest levels in adipose tissue, with lower levels expressed in many cell types, including monocytes, skeletal muscle, vascular endothelial cells, and breast, colon, and prostate epithelium. PPARγ is a dominant regulator of many aspects of fat cell biology, including adipose cell differentiation, fatty acid uptake, and lipogenesis, raising the possibility that the insulin-sensitizing effects of TZDs reflect the increased performance of TZD-treated adipose tissue as a sink for both fat and glucose. On the other hand, it is entirely possible that TZDs act primarily through PPARγ in other tissues such as muscle, liver, or the β cells of the pancreas. Global deletion of the PPARγ gene in mice results in placental dysfunction and embryonic lethality (8, 9), so resolution of this question in a definitive way will require the construction of tissue-specific knockouts.read more
Citations
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PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth
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Activation of PPARα and PPARγ by Environmental Phthalate Monoesters
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Cardiac Energy Metabolism in Obesity
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Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Inhibition of Cardiac Hypertrophy In Vitro and In Vivo
Masayuki Asakawa,Hiroyuki Takano,Toshio Nagai,Hiroki Uozumi,Hiroshi Hasegawa,Naoto Kubota,Toshihiro Saito,Yoshiaki Masuda,Takashi Kadowaki,Issei Komuro +9 more
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References
More filters
Journal ArticleDOI
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
Diabetes Control,David M. Nathan,Saul M. Genuth,John M. Lachin,Patricia A. Cleary,O Crofford,Matthew M. Davis,Larry Rand,Carolyn Siebert +8 more
TL;DR: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Journal Article
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
R C Turner,Rury R. Holman,Carole A. Cull,Irene M Stratton,David R Matthews,V Frighi,Susan E. Manley,Andrew Neil,K McElroy,D Wright,E. M. Kohner,Caroline S. Fox,D R Hadden,Z Mehta,Albert V. Smith,Z Nugent,Richard Peto,A I Adlel,Jim Mann,P A Bassett,S. Oakes,Tim Dornan,Stephen J Aldington,H Lipinski,R Collum,K Harrison,C MacIntyre,S Skinner,A Mortemore,D Nelson,S Cockley,S Levien,L Bodsworth,R Willox,T Biggs,S Dove,E Beattie,M Gradwell,S Staples,R Lam,F Taylor,L Leung,R D Carter,S M Brownlee,K E Fisher,K Islam,R. Jelfs,P A Williams,F A Williams,P J Sutton,A Ayres,Lisa Logie,C Lovatt,M A Evans,L A Stowell,I Ross,I A Kennedy,D. J. Croft,A H Keen,C Rose,M Raikou,A E Fletcher,Christopher J. Bulpitt,Clare Battersby,J S Yudkin,Richard Stevens,M R Stearn,S L Palmer,M S Hammersley,S L Franklin,R S Spivey,Jonathan C. Levy,C R Tidy,N J Bell,J Steemson,B A Barrow,R Coster,K Waring,L Nolan,E Truscott,N Walravens,L Cook,H Lampard,C Merle,P Parker,J McVittie,I Draisey,L E Murchison,Brunt Ahe.,M J Williams,D W Pearson,Petrie Xmp.,Lean Mej.,D Walmsley,F Lyall,E Christie,J Church,E Thomson,A Farrow,J M Stowers,M Stowers,K McHardy,N Patterson,Alex D. Wright,N A Levi,Shearer Aci.,Thompson Rjw.,G Taylor,S Rayton,M Bradbury,A Glover,A Smyth-Osbourne,C Parkes,J Graham,P England,S Gyde,C Eagle,B Chakrabarti,Josh Smith,J Sherwell,N. W. Oakley,M. Whitehead,G P Hollier,T. Pilkington,J Simpson,Michael W. Anderson,S Martin,J Kean,B Rice,A Rolland,J Nisbet,E M Kohner,A Dornhorst,M C Doddridge,M Dumskyij,S Walji,P Sharp,M Sleightholm,G Vanterpool,G Frost,M Roseblade,S Elliott,S Forrester,Meredith C. Foster,K Myers,R Chapman,J R Hayes,R W Henry,M S Featherston,Archbold Gpr.,M Copeland,R Harper,I Richardson,H A Davison,L Alexander,Scarpello Jhb.,D E Shiers,R J Tucker,Worthington Jrh.,S Angris,A Bates,J Walton,M Teasdale,J Browne,S Stanley,B A Davis,R C Strange,Hadden,L Kennedy,A B Atkinson,P M Bell,D R McCance,J Rutherford,A M Culbert,C Hegan,H Tennet,N Webb,I Robinson,J Holmes,S Nesbitt,A S Spathis,S Hyer,M E Nanson,L M James,J M Tyrell,C Davis,P Strugnell,M Booth,H Petrie,D Clark,S Hulland,J L Barron,B C Gould,J Singer,A Badenoch,M McGregor,L Isenberg,M Eckert,K Alibhai,E Marriot,Christopher E. Cox,R Price,M Fernandez,A Ryle,S Clarke,G Wallace,E Mehmed,J A Lankester,E Howard,A Waite,S MacFarlane,R H Greenwood,J Wilson,M J Denholm,R C Temple,K Whitfield,F Johnson,C Munroe,S Gorick,E Duckworth,M Fatman,S Rainbow,L J Borthwick,D J Wheatcroft,R J Seaman,R A Christie,W Wheatcroft,P Musk,Jennifer White,S McDougal,M Bond,P Raniga,J L Day,M J Doshi,James G. Wilson,J. Howard-Williams,H Humphreys,A Graham,K Hicks,S Hexman,P Bayliss,D Pledger,R W Newton,R T Jung,C Roxburgh,B Kilgallon,L Dick,N Waugh,S Kilby,A Ellingford,J Burns,C Fox,M C Holloway,H M Coghill,N Hein,A J Fox,W Cowan,M Richard,K Quested,S J Evans,Richard B Paisey,Brown Npr.,A J Tucker,R Paisey,F Garrett,J Hogg,P Park,K Williams,P Harvey,R Wilcocks,S Mason,J. C. Frost,C Warren,P Rocket,L Bower,J M Roland,D J Brown,J Youens,K Stanton-King,H Mungall,V Ball,W Maddison,D Donnelly,S King,P Griffin,Sidney C. Smith,S Church,Graham Dunn,Andrew D. Wilson,K Palmer,P M Brown,D Humphriss,Davidson Ajm.,Richard Rose,L Armistead,S Townsend,P Poon,Peacock Ida.,Culverwell Njc.,M H Charlton,Connolly Bps.,J Peacock,J Barrett,J Wain,W Beeston,George L. King,P G Hill,Boulton Ajm.,A M Robertson,V Katoulis,A Olukoga,H McDonald,S Kumar,F Abouaesha,B Abuaisha,E A Knowles,S Higgins,J Booker,J Sunter,K Breislin,R Parker,P Raval,J Curwell,H Davenport,G Shawcross,A Prest,J Grey,H Cole,C Sereviratne,R J Young,J R Clyne,M Gibson,I O'Connell,L M Wong,S J Wilson,K L Wright,Chris Wallace,D McDowell,A C Burden,E M Sellen,R Gregory,M Roshan,N Vaghela,M Burden,C Sherriff,S Mansingh,J Clarke,J Grenfell,Je Tooke,K. M. MacLeod,C Seamark,M Rammell,C Pym,J Stockman,C Yeo,J Piper,L Leighton,Ellen Green,M Hoyle,K Jones,A Hudson,A J James,Angela C. Shore,A Higham,B Martin,Neil Haw.,Butterfield Wjh.,Doll Wrs.,R Eastman,F R Ferris,N Kurinij,K McPherson,R F Mahler,Tom W. Meade,G Shafer,P J Watkins,H Keen,D Siegel,D J Betteridge,R D Cohen,D Currie,Julie L Darbyshire,J V Forrester,T Guppy,D G Johnston,Alistair McGuire,Mike Murphy,A M el-Nahas,B Pentecost,D Spiegelhalter,Alberti Kgmm.,R Denton,Philip Home,S Howell,Jarrett,V Marks,Michael Marmot,J D Ward,Grp Ukpds. +398 more
TL;DR: In this article, the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial were compared.
Journal ArticleDOI
Role of Insulin Resistance in Human Disease
TL;DR: The possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
Journal ArticleDOI
The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation
Mercedes Ricote,Andrew C. Li,Andrew C. Li,Timothy M. Willson,Carolyn J. Kelly,Christopher K. Glass +5 more
TL;DR: It is shown that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPar-γ ligands, suggesting that PPARS and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses.
Journal ArticleDOI
PPAR-γ agonists inhibit production of monocyte inflammatory cytokines
TL;DR: Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).