Advertisement

Lipids, Lipoproteins, and Peroxisome Proliferator Activated Receptor–δ

  • Dennis L. Sprecher
    Correspondence
    Address for reprints: Dennis L. Sprecher, MD, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406
    Affiliations
    Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania, USA; and University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Search for articles by this author
      Peroxisome proliferator activated receptors (PPARs) are nuclear receptors activated by small, lipophilic compounds. Typically resident on nuclear DNA, full activation requires heterodimer formation with retinoid X receptor and ligand binding, leading to modulation in the expression of hundreds of genes. Of the 3 described forms, (PPAR-α, PPAR-γ, and PPAR-δ), PPAR-δ has been the least investigated. Preclinical in vitro data show that activation of PPAR-δ, like PPAR-α, results in enhancement of fatty acid oxidation, leading to increased energy production in the form of adenosine triphosphate and of energy uncoupling. Microarray data in preclinical models suggest substantial PPAR-δ expression in skeletal muscle. Exercise, which induces upregulation of PPAR-δ in muscle tissue, leads to an increased requirement for an external or serum derived triacylglycerol energy source. This suggests that upregulation of skeletal muscle PPAR-δ would influence lipoprotein composition, this being the major source of combustible substrate. In the first human study using a PPAR-δ agonist, experimental data obtained with GW 501516 (a highly specific PPAR-δ agonist) suggested that upregulated enzymes critical to fatty acid oxidation in human cells enhanced fatty acid and β-oxidation in skeletal muscle.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Willson T.M.
        • Brown P.J.
        • Sternbach D.D.
        • Henke B.R.
        The PPARs: from orphan receptors to drug discovery.
        J Med Chem. 2000; 43: 527-550
        • Berger J.
        • Moller D.E.
        The mechanisms of action of PPARs.
        Annu Rev Med. 2002; 53: 409-435
        • Wahli W.
        • Braissant O.
        • Desvergne B.
        Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more.
        Chem Biol. 1995; 2: 261-266
        • Picard F.
        • Kurtev M.
        • Chung N.
        • Topark-Ngarm A.
        • Senawong T.
        • Machado de Oliveira R.
        • Leid M.
        • McBurney M.W.
        • Guarente L.
        Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ.
        Nature. 2004; 429: 771-776
        • Fabris R.
        • Nisoli E.
        • Lombardi A.M.
        • Tonello C.
        • Serra R.
        • Granzotto M.
        • Cusin I.
        • Rohner-Jeanrenaud F.
        • Federspil G.
        • Carruba M.O.
        • Vettor R.
        Preferential channeling of energy fuels toward fat rather than muscle during high free fatty acid availability in rats.
        Diabetes. 2001; 50: 601-608
        • Gilde A.J.
        • Van Bilsen M.
        Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle.
        Acta Physiol Scand. 2003; 178: 425-434
        • Kliewer S.A.
        • Xu H.E.
        • Lambert M.H.
        • Willson T.M.
        Peroxisome proliferator-activated receptors: from genes to physiology.
        Recent Prog Horm Res. 2001; 56: 239-263
        • Muoio D.M.
        • MacLean P.S.
        • Lang D.B.
        • Li S.
        • Houmard J.A.
        • Way J.M.
        • Winegar D.A.
        • Corton J.C.
        • Dohm G.L.
        • Kraus W.E.
        Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) α knock-out mice: evidence for compensatory regulation by PPAR δ.
        J Biol Chem. 2002; 277: 26089-26097
        • Lee C.H.
        • Olson P.
        • Evans R.M.
        Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors.
        Endocrinology. 2003; 144: 2201-2207
        • Luquet S.
        • Lopez-Soriano J.
        • Holst D.
        • Frederich A.
        • Melki J.
        • Rassoulzadegan M.
        • Grimaldi P.A.
        Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability.
        FASEB J. 2003; 17: 2299-2301
        • Wang Y.-X.
        • Zhang C.-L.
        • Yu R.T.
        • Cho H.K.
        • Nelson M.C.
        • Bayusga-Ocampo C.R.
        • Ham J.
        • Kang H.
        • Evans R.M.
        Regulation of muscle fiber type and running endurance by PPARδ.
        PLoS Biol. 2004; 2: e294
        • Booth F.W.
        • Thomason D.B.
        Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models.
        Physiol Rev. 1991; 71: 541-585
        • Berchtold M.W.
        • Brinkmeier H.
        • Muntener M.
        Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease.
        Physiol Rev. 2000; 80: 1215-1265
        • Tanaka T.
        • Yamamoto J.
        • Iwasaki S.
        • Asaba H.
        • Hamura H.
        • Ikeda Y.
        • Watanabe M.
        • Magoori K.
        • Ioka R.X.
        • Tachibana K.
        • et al.
        Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome.
        Proc Natl Acad Sci U S A. 2003; 100: 15924-15929
        • Wang Y.-X.
        • Lee C.H.
        • Trep S.
        • Yu R.T.
        • Ham J.
        • Kang H.
        • Evans R.M.
        Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity.
        Cell. 2003; 113: 159-170
        • Baar K.
        • Wende A.R.
        • Jones T.E.
        • Marison M.
        • Nolte L.A.
        • Chen M.
        • Kelly D.P.
        • Holloszy O.
        Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1.
        FASEB J. 2002; 16: 1879-1886
        • Holloszy J.O.
        Biochemical adaptations in muscle: effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle.
        J Biol Chem. 1967; 242: 2278-2782
        • Holst D.
        • Luquet S.
        • Nogueira V.
        • Kristiansen K.
        • Leverve X.
        • Grimaldi P.A.
        Nutritional regulation and role of peroxisome proliferator-activated receptor δ in fatty acid catabolism in skeletal muscle.
        Biochim Biophys Acta. 2003; 1633: 43-50
        • Allen D.L.
        • Harrison B.C.
        • Maass A.
        • Bell M.L.
        • Byrnes W.C.
        • Leinwand L.A.
        Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse.
        J Appl Physiol. 2001; 90: 1900-1908
        • Oliver Jr, W.R.
        • Shenk J.L.
        • Smith M.R.
        • Russell C.S.
        • Plunker K.D.
        • Bodkin N.L.
        • Lewis M.C.
        • Winegar D.A.
        • Sznaidman M.L.
        • Lambert M.H.
        • et al.
        A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport.
        Proc Natl Acad Sci U S A. 2001; 98: 5306-5311
        • Wallace J.M.
        • Schwarz M.
        • Coward P.
        • Houze J.
        • Sawyer J.K.
        • Kelley K.L.
        • Chai A.
        • Rudell L.L.
        Effects of peroxisome proliferator-activated receptor α/δ agonists on HDL-cholesterol in vervet monkeys.
        J Lipid Res. 2005; 46: 1009-1016
        • Tikkanen H.O.
        • Hamalainen E.
        • Harkonen M.
        Significance of skeletal muscle properties on fitness, long-term physical training and serum lipids.
        Atherosclerosis. 1999; 142: 367-378
        • Jarvis J.C.
        • Mokrusch T.
        • Kwende M.M.
        • Sutherland H.
        • Salmon S.
        Fast-to-slow transformation in stimulated rat muscle.
        Muscle Nerve. 1996; 19: 1469-1475
        • Pette D.
        Training effects on the contractile apparatus.
        Acta Physiol Scand. 1998; 162: 367-376
        • Hood D.A.
        Invited review: contractile activity-induced mitochondrial biogenesis in skeletal muscle.
        J Appl Physiol. 2001; 90: 1137-1157
        • Lopez-Soriano J.
        • Chiellini C.
        • Maffei M.
        • Grimaldi P.A.
        • Argiles J.M.
        Roles of skeletal muscle and peroxisome proliferator-activated receptors in the development and treatment of obesity.
        Endocr Rev. 2006; 27: 318-329
        • Kelley D.E.
        • Goodpaster B.H.
        Skeletal muscle triglyceride: an aspect of regional adiposity and insulin resistance.
        Diabetes Care. 2001; 24: 933-941
        • Phillips D.I.
        • Caddy S.
        • Ilic V.
        • Fielding B.A.
        • Frayn K.N.
        • Borthwick A.C.
        • Taylor R.
        Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects.
        Metabolism. 1996; 45: 947-950
        • Boden G.
        • Lebed B.
        • Schatz M.
        • Homko C.
        • Lemieux S.
        Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects.
        Diabetes. 2001; 50: 1612-1617
        • Koyama K.
        • Chen G.D.
        • Lee Y.
        • Unger R.H.
        Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity.
        Am J Physiol. 1997; 273: E708-E713
        • Sprecher D.L.
        • Massien C.
        • Pearce G.
        • Billin A.N.
        • Perlstein I.
        • Willson T.M.
        • Hassall D.G.
        • Ancellin N.
        • Patterson S.D.
        • Lobe D.C.
        • Johnson T.G.
        Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor δ agonist.
        Arterioscler Thromb Vasc Biol. 2007; 27: 359-365
        • Wei Z.L.
        • Kozikowski A.P.
        A short and efficient synthesis of the pharmacological research tool GW501516 for the peroxisome proliferator-activated receptor δ.
        J Org Chem. 2003; 68: 9116-9118
        • Sznaidman M.L.
        • Haffner C.D.
        • Maloney P.R.
        • Fivush A.
        • Chao E.
        • Goreham D.
        • Sierra M.L.
        • LeGrumelec C.
        • Xu H.E.
        • Montana V.G.
        • et al.
        Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)—synthesis and biological activity.
        Bioorg Med Chem Lett. 2003; 13: 1517-1521
        • von Eckardstein A.
        • Nofer J.R.
        • Assmann G.
        High density lipoproteins and arteriosclerosis: role of cholesterol efflux and reverse cholesterol transport.
        Arterioscler Thromb Vasc Biol. 2001; 21: 13-27