Regulation of lipid metabolism - PPAR regulation of lipid metabolism

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PPAR regulation of lipid metabolism

PPARs (Peroxisome Proliferator-Activated Receptors) are ligand-inducible transcription factors belonging to the nuclear hormone receptor superfamily. To regulate gene expression, PPAR forms a heterodimer with RXR (Retinoid X Receptor) and this complex binds with specific DNA response element termed PPRE (Peroxisome Proliferator response element). The PPAR group consists of three types: PPARa, PPARb (or PPARd) and PPARg. They have some differences in tissue distribution, ligand and target specificity [1], [2]. PPARa is highly expressed in tissues with intensive fatty acid oxidation (liver, heart, muscle, kidney and cells of the arterial walls) [3]. One group of its physiological ligands is long chain fatty acids [1], [3]. Activation of RXRa, heterodimeric partner of PPARa, is realized by retinoic acid [1]. PPARa is regarded as one of the key factors controlling the cellular fatty acid oxidation because it regulates the expression of many genes involved in this process [3].

The fatty acid b-oxidation takes place in mitochondria and peroxisomes. In the mitochondria, it includes following basic steps: 1) etherification of free fatty acid with cytoplasmic CoA to acyl-CoA catalyzing by acyl-CoA synthetase; 2) oxidation of acyl-CoA to enoyl-CoA catalyzing by acyl-CoA dehydrogenase; 3) hydration of enoyl-CoA with formation of 3-hydroxyacyl-CoA catalyzing by enoyl-CoA hydratase; 4) oxidation 3-hydroxyacyl-CoA to 3-oxo-acyl-CoA catalyzing by 3-hydroxyacyl-CoA dehydrogenase; 5) thiolytic cleavage of 3-oxo-acyl-CoA to acetyl-CoA and shortene acyl-CoA catalyzing by acetyl-CoA acyltransferase. The series of reactions results in splitting of two C-atoms from the molecule of fatty acid. Generated acyl-CoA enters into new oxidative cycle. Electrons generates during b-oxidation are transferred to electron transport chain. Acetyl-CoA is oxidized via citric acid cycle [3], [4]. Peroxisomal b-oxidation occurs in the same way but acyl-CoA is oxidized by acyl-CoA oxidase and energy released is not accumulated in the form of ATP but dissipates as heat [4], [5].

The PPARa/RXRa is involved in transcription regulation of a number of enzymes catalyzing these reactions (acyl-CoA synthetase, mitochondrial medium-chain acyl-CoA dehydrogenase ACADM, mitochondrial enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase HADHA [3]; peroxisomal acyl-CoA oxidase ACOX3 [4] and peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase PBE [6]). Moreover, it controls the expressions of some genes transporting fatty acids and their derivatives through cell (fatty acid transport proteins FATP [7] and CD36 [3]) and mitochondrial membranes (CPT I, CPT II) and in cytoplasm (fatty acid binding protein FABP) [3]. In addition, PPARa regulates transcription of uncoupled proteins UCP1 [8] and UCP2 [9], which serve for regulation of proton gradient on inner mitochondrial membrane [10]. The activation of all these genes by PPARa leads to increase of fatty acid uptake and utilization in cell.

References:

  1. Schoonjans K, Staels B, Auwerx J
    Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. Journal of lipid research 1996 May;37(5):907-25
  2. Neve BP, Fruchart JC, Staels B
    Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochemical pharmacology 2000 Oct 15;60(8):1245-50
  3. Barger PM, Kelly DP
    PPAR signaling in the control of cardiac energy metabolism. Trends in cardiovascular medicine 2000 Aug;10(6):238-45
  4. Reddy JK, Hashimoto T
    Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annual review of nutrition 2001;21:193-230
  5. Wanders RJ, Vreken P, Ferdinandusse S, Jansen GA, Waterham HR, van Roermund CW, Van Grunsven EG
    Peroxisomal fatty acid alpha- and beta-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochemical Society transactions 2001 May;29(Pt 2):250-67
  6. Shipley JM, Hurst CH, Tanaka SS, DeRoos FL, Butenhoff JL, Seacat AM, Waxman DJ
    trans-activation of PPARalpha and induction of PPARalpha target genes by perfluorooctane-based chemicals. Toxicological sciences : an official journal of the Society of Toxicology 2004 Jul;80(1):151-60
  7. Frohnert BI, Hui TY, Bernlohr DA
    Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. The Journal of biological chemistry 1999 Feb 12;274(7):3970-7
  8. Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M
    Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. The Journal of biological chemistry 2001 Jan 12;276(2):1486-93
  9. Mori Y, Tokutate Y, Oana F, Matsuzawa A, Akahane S, Tajima N
    Bezafibrate-induced changes over time in the expression of uncoupling protein (UCP) mRNA in the tissues: a study in spontaneously type 2 diabetic rats with visceral obesity. Journal of atherosclerosis and thrombosis 2004;11(4):224-31
  10. Rial E, González-Barroso MM
    Physiological regulation of the transport activity in the uncoupling proteins UCP1 and UCP2. Biochimica et biophysica acta 2001 Mar 1;1504(1):70-81

  1. Schoonjans K, Staels B, Auwerx J
    Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. Journal of lipid research 1996 May;37(5):907-25
  2. Neve BP, Fruchart JC, Staels B
    Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochemical pharmacology 2000 Oct 15;60(8):1245-50
  3. Barger PM, Kelly DP
    PPAR signaling in the control of cardiac energy metabolism. Trends in cardiovascular medicine 2000 Aug;10(6):238-45
  4. Reddy JK, Hashimoto T
    Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annual review of nutrition 2001;21:193-230
  5. Wanders RJ, Vreken P, Ferdinandusse S, Jansen GA, Waterham HR, van Roermund CW, Van Grunsven EG
    Peroxisomal fatty acid alpha- and beta-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochemical Society transactions 2001 May;29(Pt 2):250-67
  6. Shipley JM, Hurst CH, Tanaka SS, DeRoos FL, Butenhoff JL, Seacat AM, Waxman DJ
    trans-activation of PPARalpha and induction of PPARalpha target genes by perfluorooctane-based chemicals. Toxicological sciences : an official journal of the Society of Toxicology 2004 Jul;80(1):151-60
  7. Frohnert BI, Hui TY, Bernlohr DA
    Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. The Journal of biological chemistry 1999 Feb 12;274(7):3970-7
  8. Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M
    Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. The Journal of biological chemistry 2001 Jan 12;276(2):1486-93
  9. Mori Y, Tokutate Y, Oana F, Matsuzawa A, Akahane S, Tajima N
    Bezafibrate-induced changes over time in the expression of uncoupling protein (UCP) mRNA in the tissues: a study in spontaneously type 2 diabetic rats with visceral obesity. Journal of atherosclerosis and thrombosis 2004;11(4):224-31
  10. Rial E, González-Barroso MM
    Physiological regulation of the transport activity in the uncoupling proteins UCP1 and UCP2. Biochimica et biophysica acta 2001 Mar 1;1504(1):70-81

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